Multifunctional molecules comprising g6b binder and / or cd34 binder and uses thereof

Abstract

Multispecific molecules that include an anti-G6B antibody or binding fragment thereof, an anti- CD34 antibody or binding fragment thereof; and one, two or all of: an immune cell engager (e.g., selected from an NK cell engager, a T cell engager, a B cell engager, a dendritic cell engager, and a macrophage cell engager); a cytokine molecule; a modulator of a cytokine molecule; a stromal modifying moiety; or any combination thereof are disclosed. Additionally disclosed are nucleic acids encoding the same, and methods of treating conditions or diseases using the aforementioned molecules.

Description

MULTIFUNCTIONAL MOLECULES COMPRISING G6B BINDER AND / OR CD34 BINDER ANDUSES THEREOFRELATED APPLICATION

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 301,832 filed on January 21, 2022, the entire contents of which are hereby incorporated by reference.BACKGROUND

[0002] Myeloproliferative neoplasms (MPNs) are a group of conditions that cause blood cells to grow abnormally in the bone marrow. Common myeloproliferative neoplasms include primary or idiopathic myelofibrosis (MF), essential thrombocythemia or thrombocytosis (ET), polycythemia vera (PV), and chronic myelogenous leukemia (CML). Primary myelofibrosis is a chronic blood cancer in which excessive scar tissue forms in the bone marrow and impairs its ability to produce normal blood cells. Given the ongoing need for improved treatment of myeloproliferative neoplasms such as myelofibrosis, new compositions and treatments targeting myeloproliferative neoplasms are highly desirable.SUMMARY OF THE INVENTION

[0003] In one aspect, provided herein, inter alia, is a composition comprising an anti-G6B antibody or binding fragment thereof, or a nucleic acid encoding the anti-G6B antibody or binding fragment thereof, wherein the anti-G6B antibody or binding fragment thereof comprises a heavy chain variable domain (VH) comprising a heavy chain complementarity determining region 3 (HC CDR3) of any one of the sequences selected from the group consisting of SEQ ID NOs: 204, 208, 211, 215, 219, 223, and 227.

[0004] In some embodiments, the VH of the anti-G6B antibody or binding fragment thereof further comprises a heavy chain complementarity determining region 1 (HC CDR1) of any one of the sequences selected from the group consisting of SEQ ID NOs: 202, 206, 213, 217, 221, and 225.

[0005] In some embodiments, the VH of the anti-G6B antibody or binding fragment thereof further comprises a heavy chain complementarity determining region 2 (HC CDR2) of any one of the sequences selected from the group consisting of SEQ ID NOs: 203, 207, 210, 214, 218, 222, and 226.

[0006] In some embodiments, the anti-G6B antibody or binding fragment thereof comprises a light chain variable domain (VL) comprising a light chain complementarity determining region 3 (LC CDR3) of any one of the sequences selected from the group consisting of SEQ ID NOs: 231, 235, 239, 243, 247, 250, 254, 258, 262, 266, 270, 274, and 278.

[0007] In some embodiments, the VL of the anti-G6B antibody or binding fragment thereof further comprises a light chain complementarity determining region 1 (LC CDR1) of any one of the sequences selected from the group consisting of SEQ ID NOs: 229, 233, 237, 241, 245, 252, 256, 260, 264, 268, 272, and 276.

[0008] In some embodiments, the VL of the anti-G6B antibody or binding fragment thereof further comprises a light chain complementarity determining region 2 (LC CDR2) of any one of the sequences selected from the group consisting of SEQ ID NOs: 230, 234, 238, 242, 246, 249, 253, 257, 261, 265, 269,273, and 277.

[0009] In some embodiments, the anti-G6B antibody or binding fragment thereof comprises: (i) the VH comprising the HC CDR1 of any one of the sequences selected from the group consisting of SEQ ID NOs: 202, 206, 213, 217, 221, and 225, the HC CDR2 of any one of the sequences selected from the group consisting of SEQ ID NOs: 203, 207, 210, 214, 218, 222, and 226, and the HC CDR3 of any one of the sequences selected from the group consisting of SEQ ID NOs: 204, 208, 211, 215, 219, 223, and 227; (ii) the VL comprising the LC CDR1 of any one of the sequences selected from the group consisting of SEQ ID NOs: 229, 233, 237, 241, 245, 252, 256, 260, 264, 268, 272, and 276, the LC CDR2 of any one of the sequences selected from the group consisting of SEQ ID NOs: 230, 234, 238, 242, 246, 249, 253, 257, 261, 265, 269, 273, and 277, and the LC CDR3 of any one of the sequences selected from the group consisting of SEQ ID NOs: 231, 235, 239, 243, 247, 250, 254, 258, 262, 266, 270, 274, and 278; or (iii) any combination thereof.

[0010] In some embodiments, the anti-G6B antibody or binding fragment thereof comprises: (i) the VH comprising a HC CDR1, a HC CDR2 and a HC CDR3 of SEQ ID NOs: 202, 203, and 204, respectively; SEQ ID NOs: 206, 207, and 208, respectively; SEQ ID NOs: 206, 210, and 211, respectively; SEQ ID NOs: 213, 214, and 215, respectively; SEQ ID NOs: 217, 218, and 219, respectively; SEQ ID NOs: 221, 222, and 223, respectively; or SEQ ID NOs: 225, 226, and 227, respectively; (ii) the VL comprising a LC CDR1, a LC CDR2 and a LC CDR3 of SEQ ID NOs: 229, 230, and 231, respectively; SEQ ID NOs: 233, 234, and 235, respectively; SEQ ID NOs: 237, 238, and 239, respectively; SEQ ID NOs: 241, 242, and 243, respectively; SEQ ID NOs: 245, 246, and 247, respectively; SEQ ID NOs: 245, 249, and 250, respectively; SEQ ID NOs: 252, 253, and 254, respectively; SEQ ID NOs: 256, 257, and 258, respectively; SEQ ID NOs: 260, 261, and 262, respectively; SEQ ID NOs: 264, 265, and 266, respectively; SEQ ID NOs: 268, 269, and 270, respectively; SEQ ID NOs: 272, 273, and 274, respectively; or SEQ ID NOs: 276, 277, and 278, respectively; or (iii) any combination thereof.

[0011] In some embodiments, the anti-G6B antibody or binding fragment thereof comprises: (i) a VH comprising an amino acid sequence with at least 70% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 201, 205, 209, 212, 216, 220, and 224; (ii) a VL comprising an amino acid sequence with at least 70% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 228, 232, 236, 240, 244, 248, 251, 255, 259, 263, 267, 271, and 275; or (iii) any combination thereof.

[0012] In some embodiments, the anti-G6B antibody or binding fragment thereof comprises: (i) a VH comprising a sequence selected from the group consisting of SEQ ID NOs: 201, 205, 209, 212, 216, 220, and 224; (ii) a VL comprising a sequence selected from the group consisting of SEQ ID NOs: 228, 232, 236, 240, 244, 248, 251, 255, 259, 263, 267, 271, and 275; or (iii) any combination thereof.

[0013] In some embodiments, the anti-G6B antibody or binding fragment thereof comprises: (i) a VH of any one of the sequences of SEQ ID NOs: 201, 205, 209, 212, 216, 220, and 224; (ii) a VL of any one of the sequences of SEQ ID NOs: 228, 232, 236, 240, 244, 248, 251, 255, 259, 263, 267, 271, and 275; or (iii) any combination thereof.

[0014] In some embodiments, the anti-G6B antibody or binding fragment thereof comprises: a VH of SEQ ID NO: 201 and a VL of SEQ ID NO: 228; a VH of SEQ ID NO: 201 and aVL of SEQ ID NO: 232; a VH of SEQ ID NO : 201 and a VL of SEQ ID NO : 236; a VH of SEQ ID NO : 201 and a VL of SEQ ID NO : 240; a VH of SEQ ID NO: 201 and a VL of SEQ ID NO: 244; a VH of SEQ ID NO: 201 and a VL of SEQ ID NO: 248; a VH of SEQ ID NO: 201 and a VL of SEQ ID NO: 251; a VH of SEQ ID NO: 201 and a VL of SEQ ID NO : 255 ; a VH of SEQ ID NO : 201 and a VL of SEQ ID NO : 259; a VH of SEQ ID NO : 201 and a VL of SEQ ID NO: 263; a VH of SEQ ID NO: 201 and aVL of SEQ ID NO: 267; a VH of SEQ ID NO : 201 and a VL of SEQ ID NO : 271 ; a VH of SEQ ID NO : 201 and a VL of SEQ ID NO : 275 ; a VH of SEQ ID NO: 205 and a VL of SEQ ID NO: 228; a VH of SEQ ID NO: 205 and a VL of SEQ ID NO: 232; a VH of SEQ ID NO: 205 and a VL of SEQ ID NO: 236; a VH of SEQ ID NO: 205 and a VL of SEQ ID NO: 240; a VH of SEQ ID NO: 205 and a VL of SEQ ID NO: 244; a VH of SEQ ID NO: 205 and a VL of SEQ ID NO: 248; a VH of SEQ ID NO: 205 and a VL of SEQ ID NO: 251; a VH of SEQ ID NO: 205 and a VL of SEQ ID NO: 255; a VH of SEQ ID NO: 205 and a VL of SEQ ID NO: 259; a VH of SEQ ID NO: 205 and a VL of SEQ ID NO: 263; a VH of SEQ ID NO: 205 and a VL of SEQ ID NO: 267; a VH of SEQ ID NO : 205 and a VL of SEQ ID NO : 271 ; a VH of SEQ ID NO : 205 and a VL of SEQ ID NO : 275 ; a VH of SEQ ID NO: 209 and a VL of SEQ ID NO: 228; a VH of SEQ ID NO: 209 and a VL of SEQ ID NO: 232; a VH of SEQ ID NO: 209 and a VL of SEQ ID NO: 236; a VH of SEQ ID NO: 209 and a VL of SEQ ID NO: 240; a VH of SEQ ID NO: 209 and a VL of SEQ ID NO: 244; a VH of SEQ ID NO: 209 and a VL of SEQ ID NO: 248; a VH of SEQ ID NO: 209 and a VL of SEQ ID NO: 251; a VH of SEQ ID NO: 209 and a VL of SEQ ID NO: 255; a VH of SEQ ID NO: 209 and a VL of SEQ ID NO: 259; a VH of SEQ ID NO: 209 and a VL of SEQ ID NO: 263; a VH of SEQ ID NO: 209 and a VL of SEQ ID NO: 267; a VH of SEQ ID NO : 209 and a VL of SEQ ID NO : 271 ; a VH of SEQ ID NO : 209 and a VL of SEQ ID NO : 275 ; a VH of SEQ ID NO: 212 and a VL of SEQ ID NO: 228; a VH of SEQ ID NO: 212 and a VL of SEQ ID NO: 232; a VH of SEQ ID NO: 212 and a VL of SEQ ID NO: 236; a VH of SEQ ID NO: 212 and a VL of SEQ ID NO: 240; a VH of SEQ ID NO: 212 and a VL of SEQ ID NO: 244; a VH of SEQ ID NO: 212 and a VL of SEQ ID NO: 248; a VH of SEQ ID NO: 212 and a VL of SEQ ID NO: 251; a VH of SEQ ID NO: 212 and a VL of SEQ ID NO: 255; a VH of SEQ ID NO: 212 and a VL of SEQ ID NO: 259; a VH of SEQ ID NO: 212 and a VL of SEQ ID NO: 263; a VH of SEQ ID NO: 212 and a VL of SEQ ID NO: 267; a VH of SEQ ID NO : 212 and a VL of SEQ ID NO : 271 ; a VH of SEQ ID NO : 212 and a VL of SEQ ID NO : 275 ; a VH of SEQ ID NO: 216 and a VL of SEQ ID NO: 228; a VH of SEQ ID NO: 216 and a VL of SEQ ID NO: 232; a VH of SEQ ID NO : 216 and a VL of SEQ ID NO : 236; a VH of SEQ ID NO : 216 and a VL of SEQ ID NO : 240; a VH of SEQ ID NO: 216 and a VL of SEQ ID NO: 244; a VH of SEQ ID NO: 216 and a VL of SEQ ID NO: 248; a VH of SEQ ID NO: 216 and a VL of SEQ ID NO: 251; a VH of SEQ ID NO: 216 and a VL of SEQ ID NO: 255; a VH of SEQ ID NO: 216 and a VL of SEQ ID NO: 259; a VH of SEQ ID NO: 216 and a VL of SEQ ID NO: 263; a VH of SEQ ID NO: 216 and a VL of SEQ ID NO: 267; a VH of SEQ ID NO : 216 and a VL of SEQ ID NO : 271 ; a VH of SEQ ID NO : 216 and a VL of SEQ ID NO : 275 ; a VH of SEQ ID NO: 220 and a VL of SEQ ID NO: 228; a VH of SEQ ID NO: 220 and a VL of SEQ ID NO: 232; aVH of SEQ ID NO: 220 and a VL of SEQ ID NO: 236; a VH of SEQ ID NO: 220 and a VL of SEQ ID NO: 240; a VH of SEQ ID NO: 220 and a VL of SEQ ID NO: 244; a VH of SEQ ID NO: 220 and a VL of SEQ ID NO: 248; a VH of SEQ ID NO: 220 and a VL of SEQ ID NO: 251; a VH of SEQ ID NO: 220 and a VL of SEQ ID NO: 255; a VH of SEQ ID NO: 220 and a VL of SEQ ID NO: 259; a VH of SEQ ID NO: 220 and a VL of SEQ ID NO: 263; a VH of SEQ ID NO: 220 and a VL of SEQ ID NO: 267; a VH of SEQ ID NO : 220 and a VL of SEQ ID NO : 271 ; a VH of SEQ ID NO : 220 and a VL of SEQ ID NO : 275 ; a VH of SEQ ID NO: 224 and a VL of SEQ ID NO: 228; a VH of SEQ ID NO: 224 and a VL of SEQ ID NO: 232; a VH of SEQ ID NO: 224 and a VL of SEQ ID NO: 236; a VH of SEQ ID NO: 224 and a VL of SEQ ID NO: 240; a VH of SEQ ID NO: 224 and a VL of SEQ ID NO: 244; a VH of SEQ ID NO: 224 and a VL of SEQ ID NO: 248; a VH of SEQ ID NO: 224 and a VL of SEQ ID NO: 251; a VH of SEQ ID NO: 224 and a VL of SEQ ID NO: 255; a VH of SEQ ID NO: 224 and a VL of SEQ ID NO: 259; a VH of SEQ ID NO: 224 and a VL of SEQ ID NO: 263; a VH of SEQ ID NO: 224 and a VL of SEQ ID NO: 267; a VH of SEQ ID NO: 224 and a VL of SEQ ID NO: 271; or a VH of SEQ ID NO: 224 and a VL of SEQ ID NO: 275.

[0015] In some embodiments, the anti-G6B antibody or binding fragment thereof is a full-length antibody, a Fab, a F(ab')2, an Fv, a single chain Fv, a single domain antibody, a half arm antibody, a diabody (dAb), a bivalent antibody, a monovalent antibody, a bispecific antibody or fragment thereof, or a camelid antibody.

[0016] In some embodiments, the anti-G6B antibody or binding fragment thereof is the scFv, wherein the scFv comprises a VH and a VL operatively linked by a linker.

[0017] In some embodiments, the linker is selected from the group consisting of a cleavable linker, a non- cleavable linker, a peptide linker, a flexible linker, a rigid linker, a helical linker, and a non-helical linker.

[0018] In some embodiments, the linker is the peptide linker, and wherein the linker comprises any one of the sequences selected from the group consisting of SEQ ID NOs: 69-72 and 295.

[0019] In some embodiments, the anti-G6B antibody or binding fragment thereof is a murine, human, or humanized antibody or binding fragment thereof.

[0020] In some embodiments, the composition further comprises an antigen binding moiety, an immune cell engager, a cytokine molecule, a modulator of a cytokine molecule, a stromal modifying moiety, or any combination thereof, and wherein the immune cell engager is selected from the group consisting of a T cell engager, an NK cell engager, a B cell engager, a dendritic cell engager, and a macrophage cell engager.

[0021] In some embodiments, the anti-G6B antibody or binding fragment thereof is linked to the antigen binding moiety, the immune cell engager, the cytokine molecule, the modulator of a cytokine molecule, the stromal modifying moiety, or any combination thereof.

[0022] In some embodiments, the anti-G6B antibody or binding fragment thereof is linked to the antigen binding moiety, the immune cell engager, the cytokine molecule, the modulator of a cytokine molecule, the stromal modifying moiety, or any combination thereof by a linker.

[0023] In some embodiments, the antigen binding moiety is a tumor targeting moiety.

[0024] In some embodiments, the antigen binding moiety is an anti-CD34 antibody or binding fragmentthereof.

[0025] In another aspect, provided herein is a composition comprising an anti-CD34 antibody or binding fragment thereof, or a nucleic acid encoding the anti-CD34 antibody or binding fragment thereof, wherein the anti-CD34 antibody or binding fragment thereof comprises a heavy chain variable domain (VH) comprising a heavy chain complementarity determining region 3 (HC CDR3) of SEQ ID NO: 282.

[0026] In some embodiments, the VH of the anti-CD34 antibody or binding fragment thereof further comprises a heavy chain complementarity determining region 1 (HC CDR1) of SEQ ID NO: 281.

[0027] In some embodiments, the VH of the anti-CD34 antibody or binding fragment thereof further comprises a heavy chain complementarity determining region 2 (HC CDR2) of SEQ ID NO: 280.

[0028] In some embodiments, the anti-CD34 antibody or binding fragment thereof comprises a light chain variable domain (VL) comprising a light chain complementarity determining region 3 (LC CDR3) of SEQ ID NO: 291.

[0029] In some embodiments, the VL of the anti-CD34 antibody or binding fragment thereof further comprises a light chain complementarity determining region 1 (LC CDR1) of SEQ ID NO: 290.

[0030] In some embodiments, the VL of the anti-CD34 antibody or binding fragment thereof further comprises a light chain complementarity determining region 2 (LC CDR2) of SEQ ID NO: 289.

[0031] In some embodiments, the anti-CD34 antibody or binding fragment thereof comprises: (i) the VH comprising the HC CDR1 of SEQ ID NO: 280, the HC CDR2 of SEQ ID NO: 281, and the HC CDR3 of SEQ ID NO: 282; (ii) the VL comprising the LC CDR1 of SEQ ID NO: 289, the LC CDR2 of SEQ ID NO: 290, and the LC CDR3 of SEQ ID NO: 291; or (iii) any combination thereof.

[0032] In some embodiments, the anti-CD34 antibody or binding fragment thereof comprises: (i) a VH comprising an amino acid sequence with at least 70% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 279, 283, 284, 285, 286, and 287; (ii) a VL comprising an amino acid sequence with at least 70% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 288, 292, 293, and 294; or (iii) any combination thereof.

[0033] In some embodiments, the anti-CD34 antibody or binding fragment thereof comprises: (i) a VH comprising a sequence selected from the group consisting of SEQ ID NOs: 279, 283, 284, 285, 286, and 287; (ii) a VL comprising a sequence selected from the group consisting of SEQ ID NOs: 292, 293, and 294; or (iii) any combination thereof.

[0034] In some embodiments, the anti-CD34 antibody or binding fragment thereof comprises: (i) a VH of any one of the sequence of SEQ ID NOs: 279, 283, 284, 285, 286, and 287; (ii) a VL of any one of the sequence of SEQ ID NOs: 292, 293, and 294; or (iii) any combination thereof.

[0035] In some embodiments, the anti-CD34 antibody or binding fragment thereof comprises: a VH of SEQ ID NO: 279 and a VL of SEQ ID NO: 292; a VH of SEQ ID NO: 279 and a VL of SEQ ID NO: 293; a VH of SEQ ID NO: 279 and a VL of SEQ ID NO: 294; a VH of SEQ ID NO: 283 and a VL of SEQ ID NO: 292; a VH of SEQ ID NO: 283 and a VL of SEQ ID NO: 293; a VH of SEQ ID NO: 283 and a VL of SEQ ID NO: 294; a VH of SEQ ID NO: 284 and a VL of SEQ ID NO: 292; a VH of SEQ ID NO: 284 and a VLof SEQ ID NO: 293; a VH of SEQ ID NO: 284 and a VL of SEQ ID NO: 294; a VH of SEQ ID NO: 285 and a VL of SEQ ID NO: 292; a VH of SEQ ID NO: 285 and a VL of SEQ ID NO: 293; a VH of SEQ ID NO: 285 and a VL of SEQ ID NO: 294; a VH of SEQ ID NO: 286 and a VL of SEQ ID NO: 292; a VH of SEQ ID NO: 286 and a VL of SEQ ID NO: 293; a VH of SEQ ID NO: 286 and a VL of SEQ ID NO: 294; a VH of SEQ ID NO: 287 and a VL of SEQ ID NO: 292; a VH of SEQ ID NO: 287 and a VL of SEQ ID NO: 293; or a VH of SEQ ID NO: 287 and a VL of SEQ ID NO: 294.

[0036] In some embodiments, the anti-CD34 antibody or binding fragment thereof is a full-length antibody, a Fab, a F(ab')2, an Fv, a single chain Fv, a single domain antibody, a half arm antibody, a diabody (dAb), a bivalent antibody, a monovalent antibody, a bispecific antibody or fragment thereof, or a camelid antibody.

[0037] In some embodiments, the anti-CD34 antibody or binding fragment thereof is the scFv, wherein the scFv comprises a VH and a VL operatively linked by a linker.

[0038] In some embodiments, the linker is selected from the group consisting of a cleavable linker, a non- cleavable linker, a peptide linker, a flexible linker, a rigid linker, a helical linker, and a non-helical linker.

[0039] In some embodiments, the linker is the peptide linker, and wherein the linker comprises any one of the sequences selected from the group consisting of SEQ ID NOs: 69-72 and 295.

[0040] In some embodiments, the anti-CD34 antibody or binding fragment thereof is a murine, human, or humanized antibody or binding fragment thereof.

[0041] In some embodiments, the composition further comprises an antigen binding moiety, tin immune cell engager, a cytokine molecule, a modulator of a cytokine molecule, a stromal modifying moiety , or any com bination thereof, and wherein the immune cell engager is selected from the group consisting of a T cell engager, an NK cell engager, a B cell engager, a dendritic cell engager, and a macrophage cell engager.

[0042] In some embodiments, the anti-CD34 antibody or binding fragment thereof is linked to the antigen binding moiety, the immune cell engager, the cytokine molecule, the modulator of a cytokine molecule, the stromal modifying moiety, or any combination thereof.

[0043] In some embodiments, the anti-CD34 antibody or binding fragment thereof is linked to the antigen binding moiety, the immune cell engager, the cytokine molecule, the modulator of a cytokine molecule, the stromal modifying moiety, or any combination thereof by a linker.

[0044] In some embodiments, the antigen binding moiety is a tumor targeting moiety.

[0045] In some embodiments, the antigen binding moiety is an anti-G6B antibody or binding fragment thereof.

[0046] In another aspect, provided herein is a composition comprising a multifunctional molecule or a nucleic acid encoding the multifunctional molecule, wherein the multifunctional molecule comprises an anti- G6B antibody or binding fragment thereof linked to an antigen binding moiety, wherein the anti-G6B antibody or binding fragment thereof comprises a heavy chain variable domain (VH) comprising a heavy chain complementarity determining region 3 (HC CDR3) of any one of the sequences selected from the group consisting of SEQ ID NOs: 204, 208, 211, 215, 219, 223, and 227.

[0047] In some embodiments, the antigen binding moiety is an anti-CD34 antibody or binding fragment thereof.

[0048] In some embodiments, the anti-CD34 antibody or binding fragment thereof comprises a heavy chain variable domain (VH) comprising a heavy chain complementarity determining region 3 (HC CDR3) of SEQ ID NO: 282.

[0049] In another aspect, provided herein is a composition comprising a multifunctional molecule or a nucleic acid encoding the multifunctional molecule, wherein the multifunctional molecule comprises an anti- CD34 antibody or binding fragment thereof linked to an antigen binding moiety, wherein the anti-CD34 antibody or binding fragment thereof comprises a heavy chain variable domain (VH) comprising a heavy chain complementarity determining region 3 (HC CDR3) of SEQ ID NO: 282.

[0050] In some embodiments, the antigen binding moiety is an anti-G6B antibody or binding fragment thereof.

[0051] In some embodiments, the anti-G6B antibody or binding fragment thereof comprises a heavy chain variable domain (VH) comprising a heavy chain complementarity determining region 3 (HC CDR3) of any one of the sequences selected from the group consisting of SEQ ID NOs: 204, 208, 211, 215, 219, 223, and 227.

[0052] In some embodiments, the VH of the anti-G6B antibody or binding fragment thereof further comprises a heavy chain complementarity determining region 1 (HC CDR1) of any one of the sequences selected from the group consisting of SEQ ID NOs: 202, 206, 213, 217, 221, and 225.

[0053] In some embodiments, the VH of the anti-G6B antibody or binding fragment thereof further comprises a heavy chain complementarity determining region 2 (HC CDR2) of any one of the sequences selected from the group consisting of SEQ ID NOs: 203, 207, 210, 214, 218, 222, and 226.

[0054] In some embodiments, the anti-G6B antibody or binding fragment thereof comprises a light chain variable domain (VL) comprising a light chain complementarity determining region 3 (LC CDR3) of any one of the sequences selected from the group consisting of SEQ ID NOs: 231, 235, 239, 243, 247, 250, 254, 258, 262, 266, 270, 274, and 278.

[0055] In some embodiments, the VL of the anti-G6B antibody or binding fragment thereof further comprises a light chain complementarity determining region 1 (LC CDR1) of any one of the sequences selected from the group consisting of SEQ ID NOs: 229, 233, 237, 241, 245, 252, 256, 260, 264, 268, 272, and 276.

[0056] In some embodiments, the VL of the anti-G6B antibody or binding fragment thereof further comprises a light chain complementarity determining region 2 (LC CDR2) of any one of the sequences selected from the group consisting of SEQ ID NOs: 230, 234, 238, 242, 246, 249, 253, 257, 261, 265, 269, 273, and 277.

[0057] In some embodiments, the anti-G6B antibody or binding fragment thereof comprises: (i) the VH comprising the HC CDR1 of any one of the sequences selected from the group consisting of SEQ ID NOs: 202, 206, 213, 217, 221, and 225, the HC CDR2 of any one of the sequences selected from the groupconsisting of SEQ ID NOs: 203, 207, 210, 214, 218, 222, and 226, and the HC CDR3 of any one of the sequences selected from the group consisting of SEQ ID NOs: 204, 208, 211, 215, 219, 223, and 227; (ii) the VL comprising the LC CDR1 of any one of the sequences selected from the group consisting of SEQ ID NOs: 229, 233, 237, 241, 245, 252, 256, 260, 264, 268, 272, and 276, the LC CDR2 of any one of the sequences selected from the group consisting of SEQ ID NOs: 230, 234, 238, 242, 246, 249, 253, 257, 261, 265, 269, 273, and 277, and the LC CDR3 of any one of the sequences selected from the group consisting of SEQ ID NOs: 231, 235, 239, 243, 247, 250, 254, 258, 262, 266, 270, 274, and 278; or (iii) any combination thereof.

[0058] In some embodiments, the anti-G6B antibody or binding fragment thereof comprises: (i) the VH comprising a HC CDR1, a HC CDR2 and a HC CDR3 of SEQ ID NOs: 202, 203, and 204, respectively;SEQ ID NOs: 206, 207, and 208, respectively; SEQ ID NOs: 206, 210, and 211, respectively; SEQ ID NOs: 213, 214, and 215, respectively; SEQ ID NOs: 217, 218, and 219, respectively; SEQ ID NOs: 221, 222, and 223, respectively; or SEQ ID NOs: 225, 226, and 227, respectively; (ii) the VL comprising a LC CDR1, a LC CDR2 and a LC CDR3 of SEQ ID NOs: 229, 230, and 231, respectively; SEQ ID NOs: 233, 234, and 235, respectively; SEQ ID NOs: 237, 238, and 239, respectively; SEQ ID NOs: 241, 242, and 243, respectively; SEQ ID NOs: 245, 246, and 247, respectively; SEQ ID NOs: 245, 249, and 250, respectively; SEQ ID NOs: 252, 253, and 254, respectively; SEQ ID NOs: 256, 257, and 258, respectively; SEQ ID NOs: 260, 261, and 262, respectively; SEQ ID NOs: 264, 265, and 266, respectively; SEQ ID NOs: 268, 269, and 270, respectively; SEQ ID NOs: 272, 273, and 274, respectively; or SEQ ID NOs: 276, 277, and 278, respectively; or (iii) any combination thereof.

[0059] In some embodiments, the anti-G6B antibody or binding fragment thereof comprises: (i) a VH comprising an amino acid sequence with at least 70% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 201, 205, 209, 212, 216, 220, and 224; (ii) a VL comprising an amino acid sequence with at least 70% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 228, 232, 236, 240, 244, 248, 251, 255, 259, 263, 267, 271, and 275; or (iii) any combination thereof.

[0060] In some embodiments, the anti-G6B antibody or binding fragment thereof comprises: (i) a VH comprising a sequence selected from the group consisting of SEQ ID NOs: 201, 205, 209, 212, 216, 220, and 224; (ii) a VL comprising a sequence selected from the group consisting of SEQ ID NOs: 228, 232, 236, 240, 244, 248, 251, 255, 259, 263, 267, 271, and 275; or (iii) any combination thereof.

[0061] In some embodiments, the anti-G6B antibody or binding fragment thereof comprises: (i) a VH of any one of the sequences of SEQ ID NOs: 201, 205, 209, 212, 216, 220, and 224; (ii) a VL of any one of the sequences of SEQ ID NOs: 228, 232, 236, 240, 244, 248, 251, 255, 259, 263, 267, 271, and 275; or (iii) any combination thereof.

[0062] In some embodiments, the anti-G6B antibody or binding fragment thereof comprises: a VH of SEQ ID NO: 201 and a VL of SEQ ID NO: 228; a VH of SEQ ID NO: 201 and a VL of SEQ ID NO: 232; a VH of SEQ ID NO : 201 and a VL of SEQ ID NO : 236; a VH of SEQ ID NO : 201 and a VL of SEQ ID NO : 240; a VH of SEQ ID NO: 201 and a VL of SEQ ID NO: 244; a VH of SEQ ID NO: 201 and a VL of SEQID NO: 248; a VH of SEQ ID NO: 201 and a VL of SEQ ID NO: 251; a VH of SEQ ID NO: 201 and a VL of SEQ ID NO : 255 ; a VH of SEQ ID NO : 201 and a VL of SEQ ID NO : 259; a VH of SEQ ID NO : 201 and a VL of SEQ ID NO: 263; a VH of SEQ ID NO: 201 and aVL of SEQ ID NO: 267; a VH of SEQ ID NO : 201 and a VL of SEQ ID NO : 271 ; a VH of SEQ ID NO : 201 and a VL of SEQ ID NO : 275 ; a VH of SEQ ID NO: 205 and a VL of SEQ ID NO: 228; a VH of SEQ ID NO: 205 and a VL of SEQ ID NO: 232; a VH of SEQ ID NO: 205 and a VL of SEQ ID NO: 236; a VH of SEQ ID NO: 205 and a VL of SEQ ID NO: 240; a VH of SEQ ID NO: 205 and a VL of SEQ ID NO: 244; a VH of SEQ ID NO: 205 and a VL of SEQ ID NO: 248; a VH of SEQ ID NO: 205 and a VL of SEQ ID NO: 251; a VH of SEQ ID NO: 205 and a VL of SEQ ID NO: 255; a VH of SEQ ID NO: 205 and a VL of SEQ ID NO: 259; a VH of SEQ ID NO: 205 and a VL of SEQ ID NO: 263; a VH of SEQ ID NO: 205 and a VL of SEQ ID NO: 267; a VH of SEQ ID NO : 205 and a VL of SEQ ID NO : 271 ; a VH of SEQ ID NO : 205 and a VL of SEQ ID NO : 275 ; a VH of SEQ ID NO: 209 and a VL of SEQ ID NO: 228; a VH of SEQ ID NO: 209 and a VL of SEQ ID NO: 232; a VH of SEQ ID NO: 209 and a VL of SEQ ID NO: 236; a VH of SEQ ID NO: 209 and a VL of SEQ ID NO: 240; a VH of SEQ ID NO: 209 and a VL of SEQ ID NO: 244; a VH of SEQ ID NO: 209 and a VL of SEQ ID NO: 248; a VH of SEQ ID NO: 209 and a VL of SEQ ID NO: 251; a VH of SEQ ID NO: 209 and a VL of SEQ ID NO: 255; a VH of SEQ ID NO: 209 and a VL of SEQ ID NO: 259; a VH of SEQ ID NO: 209 and a VL of SEQ ID NO: 263; a VH of SEQ ID NO: 209 and a VL of SEQ ID NO: 267; a VH of SEQ ID NO : 209 and a VL of SEQ ID NO : 271 ; a VH of SEQ ID NO : 209 and a VL of SEQ ID NO : 275 ; a VH of SEQ ID NO: 212 and a VL of SEQ ID NO: 228; a VH of SEQ ID NO: 212 and a VL of SEQ ID NO: 232; a VH of SEQ ID NO: 212 and a VL of SEQ ID NO: 236; a VH of SEQ ID NO: 212 and a VL of SEQ ID NO: 240; a VH of SEQ ID NO: 212 and a VL of SEQ ID NO: 244; a VH of SEQ ID NO: 212 and a VL of SEQ ID NO: 248; a VH of SEQ ID NO: 212 and a VL of SEQ ID NO: 251; a VH of SEQ ID NO: 212 and a VL of SEQ ID NO: 255; a VH of SEQ ID NO: 212 and a VL of SEQ ID NO: 259; a VH of SEQ ID NO: 212 and a VL of SEQ ID NO: 263; a VH of SEQ ID NO: 212 and a VL of SEQ ID NO: 267; a VH of SEQ ID NO : 212 and a VL of SEQ ID NO : 271 ; a VH of SEQ ID NO : 212 and a VL of SEQ ID NO : 275 ; a VH of SEQ ID NO: 216 and a VL of SEQ ID NO: 228; a VH of SEQ ID NO: 216 and a VL of SEQ ID NO: 232; a VH of SEQ ID NO : 216 and a VL of SEQ ID NO : 236; a VH of SEQ ID NO : 216 and a VL of SEQ ID NO : 240; a VH of SEQ ID NO: 216 and a VL of SEQ ID NO: 244; a VH of SEQ ID NO: 216 and a VL of SEQ ID NO: 248; a VH of SEQ ID NO: 216 and a VL of SEQ ID NO: 251; a VH of SEQ ID NO: 216 and a VL of SEQ ID NO: 255; a VH of SEQ ID NO: 216 and a VL of SEQ ID NO: 259; a VH of SEQ ID NO: 216 and a VL of SEQ ID NO: 263; a VH of SEQ ID NO: 216 and a VL of SEQ ID NO: 267; a VH of SEQ ID NO : 216 and a VL of SEQ ID NO : 271 ; a VH of SEQ ID NO : 216 and a VL of SEQ ID NO : 275 ; a VH of SEQ ID NO: 220 and a VL of SEQ ID NO: 228; a VH of SEQ ID NO: 220 and a VL of SEQ ID NO: 232; a VH of SEQ ID NO: 220 and a VL of SEQ ID NO: 236; a VH of SEQ ID NO: 220 and a VL of SEQ ID NO: 240; a VH of SEQ ID NO: 220 and a VL of SEQ ID NO: 244; a VH of SEQ ID NO: 220 and a VL of SEQ ID NO: 248; a VH of SEQ ID NO: 220 and a VL of SEQ ID NO: 251; a VH of SEQ ID NO: 220 and a VL of SEQ ID NO: 255; a VH of SEQ ID NO: 220 and a VL of SEQ ID NO: 259; a VH of SEQ ID NO: 220and a VL of SEQ ID NO: 263; a VH of SEQ ID NO: 220 and a VL of SEQ ID NO: 267; a VH of SEQ ID NO : 220 and a VL of SEQ ID NO : 271 ; a VH of SEQ ID NO : 220 and a VL of SEQ ID NO : 275 ; a VH of SEQ ID NO: 224 and a VL of SEQ ID NO: 228; a VH of SEQ ID NO: 224 and a VL of SEQ ID NO: 232; a VH of SEQ ID NO: 224 and a VL of SEQ ID NO: 236; a VH of SEQ ID NO: 224 and a VL of SEQ ID NO: 240; a VH of SEQ ID NO: 224 and a VL of SEQ ID NO: 244; a VH of SEQ ID NO: 224 and a VL of SEQ ID NO: 248; a VH of SEQ ID NO: 224 and a VL of SEQ ID NO: 251; a VH of SEQ ID NO: 224 and a VL of SEQ ID NO: 255; a VH of SEQ ID NO: 224 and a VL of SEQ ID NO: 259; a VH of SEQ ID NO: 224 and a VL of SEQ ID NO: 263; a VH of SEQ ID NO: 224 and a VL of SEQ ID NO: 267; a VH of SEQ ID NO: 224 and a VL of SEQ ID NO: 271; or a VH of SEQ ID NO: 224 and a VL of SEQ ID NO: 275.

[0063] In some embodiments, the VH of the anti-CD34 antibody or binding fragment thereof further comprises a heavy chain complementarity determining region 1 (HC CDR1) of SEQ ID NO: 281.

[0064] In some embodiments, the VH of the anti-CD34 antibody or binding fragment thereof further comprises a heavy chain complementarity determining region 2 (HC CDR2) of SEQ ID NO: 280.

[0065] In some embodiments, the anti-CD34 antibody or binding fragment thereof comprises a light chain variable domain (VL) comprising a light chain complementarity determining region 3 (LC CDR3) of SEQ ID NO: 291.

[0066] In some embodiments, the VL of the anti-CD34 antibody or binding fragment thereof further comprises a light chain complementarity determining region 1 (LC CDR1) of SEQ ID NO: 290.

[0067] In some embodiments, the VL of the anti-CD34 antibody or binding fragment thereof further comprises a light chain complementarity determining region 2 (LC CDR2) of SEQ ID NO: 289.

[0068] In some embodiments, the anti-CD34 antibody or binding fragment thereof comprises: (i) the VH comprising the HC CDR1 of SEQ ID NO: 280, the HC CDR2 of SEQ ID NO: 281, and the HC CDR3 of SEQ ID NO: 282; (ii) the VL comprising the LC CDR1 of SEQ ID NO: 289, the LC CDR2 of SEQ ID NO: 290, and the LC CDR3 of SEQ ID NO: 291; or (iii) any combination thereof.

[0069] In some embodiments, the anti-CD34 antibody or binding fragment thereof comprises: (i) a VH comprising an amino acid sequence with at least 70% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 279, 283, 284, 285, 286, and 287; (ii) a VL comprising an amino acid sequence with at least 70% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 288, 292, 293, and 294; or (iii) any combination thereof.

[0070] In some embodiments, the anti-CD34 antibody or binding fragment thereof comprises: (i) a VH comprising a sequence selected from the group consisting of SEQ ID NOs: 279, 283, 284, 285, 286, and 287; (ii) a VL comprising a sequence selected from the group consisting of SEQ ID NOs: 288, 292, 293, and 294; or (iii) any combination thereof.

[0071] In some embodiments, the anti-CD34 antibody or binding fragment thereof comprises: (i) a VH of any one of the sequence of SEQ ID NOs: 279, 283, 284, 285, 286, and 287; (ii) a VL of any one of the sequence of SEQ ID NOs: 288, 292, 293, and 294; or (iii) any combination thereof.

[0072] In some embodiments, the anti-CD34 antibody or binding fragment thereof comprises: a VH ofSEQ ID NO: 279 and a VL of SEQ ID NO: 292; a VH of SEQ ID NO: 279 and a VL of SEQ ID NO: 293; a VH of SEQ ID NO: 279 and a VL of SEQ ID NO: 294; a VH of SEQ ID NO: 283 and a VL of SEQ ID NO: 292; a VH of SEQ ID NO: 283 and a VL of SEQ ID NO: 293; a VH of SEQ ID NO: 283 and a VL of SEQ ID NO: 294; a VH of SEQ ID NO: 284 and a VL of SEQ ID NO: 292; a VH of SEQ ID NO: 284 and a VL of SEQ ID NO: 293; a VH of SEQ ID NO: 284 and a VL of SEQ ID NO: 294; a VH of SEQ ID NO: 285 and a VL of SEQ ID NO: 292; a VH of SEQ ID NO: 285 and a VL of SEQ ID NO: 293; a VH of SEQ ID NO: 285 and a VL of SEQ ID NO: 294; a VH of SEQ ID NO: 286 and a VL of SEQ ID NO: 292; a VH of SEQ ID NO: 286 and a VL of SEQ ID NO: 293; a VH of SEQ ID NO: 286 and a VL of SEQ ID NO: 294; a VH of SEQ ID NO: 287 and a VL of SEQ ID NO: 292; a VH of SEQ ID NO: 287 and a VL of SEQ ID NO: 293; or a VH of SEQ ID NO: 287 and a VL of SEQ ID NO: 294. 0073] In some embodiments, the multifunctional molecule further comprises: (i) a constant heavy chain 1 domain (CHI) linked to the VH of anti-G6B antibody or binding fragment thereof, a CHI linked to the VH of the anti-CD34 antibody or binding fragment thereof, or any combination thereof; (ii) a constant light chain domain (CL) linked to the VL of the anti-G6B antibody or binding fragment thereof, a CL linked to the VL of the anti-CD34 antibody or binding fragment thereof, or any combination thereof; or (iii) any combination thereof.

[0074] In some embodiments, the CHI linked to the VH of anti-G6B antibody or binding fragment thereof and the CHI linked to the VH of the anti-CD34 antibody or binding fragment thereof are independently a CHI of IgGl, IgG2, IgG3, IgGAl, IgGA2, IgG4, IgJ, IgM, IgD, or IgE.

[0075] In some embodiments, the CHI linked to the VH of anti-G6B antibody or binding fragment thereof and the CHI linked to the VH of the anti-CD34 antibody or binding fragment thereof independently comprise any one of the CHI sequences selected from the group consisting of SEQ ID NOs: 299, 300, and 302-309.

[0076] In some embodiments, the CL linked to the VL of the anti-G6B antibody or binding fragment thereof and the CL linked to the VL of the anti-CD34 antibody or binding fragment thereof are independently a CL of a lambda light chain or a CL of a kappa light chain.

[0077] In some embodiments, the CL linked to the VL of the anti-G6B antibody or binding fragment thereof and the CL linked to the VL of the anti-CD34 antibody or binding fragment thereof independently comprise any one of the sequences selected from the group consisting of SEQ ID NOs: 297 and 298.

[0078] In some embodiments, the anti-G6B antibody or binding fragment thereof and the anti-CD34 antibody or binding fragment thereof is covalently linked or non-covalently linked.

[0079] In some embodiments, the multifunctional molecule comprises a first polypeptide comprising (i) the anti-G6B antibody or binding fragment thereof linked to the anti-CD34 antibody or binding fragment thereof; (ii) a first portion of the anti-G6B antibody or binding fragment thereof linked to a first portion of the anti-CD34 antibody or binding fragment thereof, wherein the multifunctional molecule further comprises a second polypeptide comprising a second portion of the anti-G6B antibody or binding fragment thereof and a third polypeptide comprising a second portion of the anti-CD34 antibody or binding fragment thereof; (iii)a first portion of the anti-G6B antibody or binding fragment thereof linked to the anti-CD34 antibody or binding fragment thereof wherein the multifunctional molecule further comprises a second polypeptide comprising a second portion of the anti-G6B antibody or binding fragment thereof; or (iv) the anti-G6B antibody or binding fragment thereof linked to a first portion of the anti-CD34 antibody or binding fragment thereof, wherein the multifunctional molecule further comprises a second polypeptide comprising a second portion of the anti-CD34 antibody or binding fragment thereof. 0080] In some embodiments, the anti-G6B antibody or binding fragment thereof and the anti-CD34 antibody or binding fragment thereof, the first portion of the anti-G6B antibody or binding fragment thereof and the first portion of the anti-CD34 antibody or binding fragment thereof, the first portion of the anti-G6B antibody or binding fragment thereof and the anti-CD34 antibody or binding fragment thereof, or the anti- G6B antibody or binding fragment thereof and the first portion of the anti-CD34 antibody or binding fragment thereof are independently linked by a linker.

[0081] In some embodiments, the multifunctional molecule comprises at least two non-contiguous polypeptide chains.

[0082] In some embodiments, a first polypeptide comprises a first member of a dimerization module and a second polypeptide comprises a second member of the dimerization module, wherein the first polypeptide and the second polypeptide form a complex via the first member of the dimerization module and the second member of the dimerization module.

[0083] In some embodiments, the first member of the dimerization module is a first Fc region, and the second member of the dimerization module is a second Fc region.

[0084] In some embodiments, the first Fc region and the second Fc region are independently an IgGl Fc region or fragment thereof, an IgG2 Fc region or fragment thereof, an IgG3 Fc region or fragment thereof, an IgGAl Fc region or fragment thereof, an IgGA2 Fc region or fragment thereof, an IgG4 Fc region or fragment thereof, an IgJ Fc region or fragment thereof, an IgM Fc region or fragment thereof, an IgD Fc region or fragment thereof, or an IgE Fc region or fragment thereof.

[0085] In some embodiments, the first Fc region and the second Fc region independently comprise any one of the Fc sequences selected from the group consisting of SEQ ID NOs: 302-307.

[0086] In some embodiments, the first Fc region is an engineered first Fc region comprising a knob and the second Fc region is an engineered second Fc region comprising a hole, or wherein the first Fc region is an engineered first Fc region comprising a hole and the second Fc region is an engineered second Fc region comprising a knob.

[0087] In some embodiments, the engineered first Fc region comprises the sequence of SEQ ID NO: 310 or SEQ ID NO: 312 and the engineered second Fc region comprises the sequence of SEQ ID NO: 311 or SEQ ID NO: 313, or wherein the engineered first Fc region comprises the sequence of SEQ ID NO: 311 or SEQ ID NO: 313 and the engineered second Fc region comprises the sequence of SEQ ID NO: 310 or SEQ ID NO: 312.

[0088] In some embodiments, the multifunctional molecule comprises the first polypeptide comprisingthe anti-G6B antibody or binding fragment thereof, and the second polypeptide comprising the anti-CD34 antibody or binding fragment thereof, wherein: (i) the first polypeptide comprises the anti-G6B antibody or binding fragment thereof linked to the first member of the dimerization module, and the second polypeptide comprises the anti-CD34 antibody or binding fragment thereof linked to the second member of the dimerization module; (ii) the first polypeptide comprises a first portion of the anti-G6B antibody or binding fragment thereof linked to the first member of the dimerization module, and the second polypeptide comprises a first portion of the anti-CD34 antibody or binding fragment thereof linked to the second member of the dimerization module; wherein the multifunctional molecule further comprises a third polypeptide comprising a second portion of the anti-G6B antibody or binding fragment thereof and a fourth polypeptide comprising a second portion of the anti-CD34 antibody or binding fragment thereof; (iii) the first polypeptide comprises a first portion of the anti-G6B antibody or binding fragment thereof linked to the first member of the dimerization module, and the second polypeptide comprises the anti-CD34 antibody or binding fragment thereof linked to the second member of the dimerization module; wherein the multifunctional molecule further comprises a third polypeptide comprising a second portion of the anti-G6B antibody or binding fragment thereof; or (iv) the first polypeptide comprises the anti-G6B antibody or binding fragment thereof linked to the first member of the dimerization module, and the second polypeptide comprises a first portion of the anti-CD34 antibody or binding fragment thereof linked to the second member of the dimerization module; wherein the multifunctional molecule further comprises a third polypeptide comprising a second portion of the anti-CD34 antibody or binding fragment thereof. 0089 In some embodiments, the anti-G6B antibody or binding fragment thereof and the first member of the dimerization module, the anti-CD34 antibody or binding fragment thereof and the second member of the dimerization module, the first portion of the anti-G6B antibody or binding fragment thereof and the first member of the dimerization module, and the first portion of the anti-CD34 antibody or binding fragment thereof and the second member of the dimerization module are independently linked by a linker.

[0090] In some embodiments, the multifunctional molecule comprises the first polypeptide comprising the anti-G6B antibody or binding fragment thereof and the anti-CD34 antibody or binding fragment thereof, wherein the first polypeptide comprises: (i) the anti-G6B antibody or binding fragment thereof linked to the first member of the dimerization module linked to the anti-CD34 antibody or binding fragment thereof; (ii) a first portion of the anti-G6B antibody or binding fragment thereof linked to the first member of the dimerization module linked to a first portion of the anti-CD34 antibody or binding fragment thereof, wherein the multifunctional molecule further comprises a third polypeptide comprising a second portion of the anti- G6B antibody or binding fragment thereof and a fourth polypeptide comprising a second portion of the anti- CD34 antibody or binding fragment thereof; (iii) a first portion of the anti-G6B antibody or binding fragment thereof linked to the first member of the dimerization module linked to the anti-CD34 antibody or binding fragment thereof, wherein the multifunctional molecule further comprises a third polypeptide comprising a second portion of the anti-G6B antibody or binding fragment thereof; or (iv) the anti-G6B antibody or binding fragment thereof linked to the first member of the dimerization module linked to a firstportion of the anti-CD34 antibody or binding fragment thereof, wherein the multifunctional molecule further comprises a third polypeptide comprising a second portion of the anti-CD34 antibody or binding fragment thereof.

[0091] In some embodiments, the anti-G6B antibody or binding fragment thereof and the first member of the dimerization module, the anti-CD34 antibody or binding fragment thereof and the first member of the dimerization module, the first portion of the anti-G6B antibody or binding fragment thereof and the first member of the dimerization module, and the first portion of the anti-CD34 antibody or binding fragment thereof and the first member of the dimerization module are independently linked by a linker.

[0092] In some embodiments, the anti-G6B antibody or binding fragment thereof, the anti-CD34 antibody or binding fragment thereof, or any combination thereof is a full-length antibody, a Fab, a F(ab')2, an Fv, a single chain Fv, a single domain antibody, a half arm antibody, a diabody (dAb), a bivalent antibody, a monovalent antibody, a bispecific antibody or fragment thereof, or a camelid antibody.

[0093] In some embodiments, the anti-G6B antibody or binding fragment thereof and the anti-CD34 antibody or binding fragment thereof are independently the Fab or the scFv.

[0094] In some embodiments, the anti-G6B antibody or binding fragment thereof and the anti-CD34 antibody or binding fragment thereof are independently the scFv, and wherein the VH and VL of the anti- G6B antibody or binding fragment thereof, and the VH and VL of the anti-CD34 antibody or binding fragment thereof are independently linked by a linker.

[0095] In some embodiments, the first portion of the anti-G6B antibody or binding fragment thereof and the first portion of the anti-CD34 antibody or binding fragment thereof are independently the VH of the anti- G6B antibody or binding fragment thereof and the VH of the anti-CD34 antibody or binding fragment thereof, respectively, and the second portion of the anti-G6B antibody or binding fragment thereof and the second portion of the anti-CD34 antibody or binding fragment thereof are independently the VL of the anti- G6B antibody or binding fragment thereof and the VL of the anti-CD34 antibody or binding fragment thereof, respectively; or wherein the first portion of the anti-G6B antibody or binding fragment thereof and the first portion of the anti-CD34 antibody or binding fragment thereof are independently the VL of the anti- G6B antibody or binding fragment thereof and the VL of the anti-CD34 antibody or binding fragment thereof, respectively, and the second portion of the anti-G6B antibody or binding fragment thereof and the second portion of the anti-CD34 antibody or binding fragment thereof are independently the VH of the anti- G6B antibody or binding fragment thereof and the VH of the anti-CD34 antibody or binding fragment thereof, respectively.

[0096] In some embodiments, the anti-G6B antibody or binding fragment thereof, the anti-CD34 antibody or binding fragment thereof, or any combination thereof is independently a murine, human, or humanized antibody or binding fragment thereof.

[0097] In some embodiments, the multifunctional molecule further comprises any one selected from the group consisting of an immune cell engager, a cytokine molecule, a modulator of a cytokine molecule, a stromal modifying moiety, a tumor targeting moiety, and any combination thereof, wherein the immune cellengager is selected from the group consisting of a T cell engager, an NK cell engager, a B cell engager, a macrophage cell engager, and a dendritic cell engager.

[0098] In some embodiments, the immune cell engager, the cytokine molecule, the modulator of a cytokine molecule, the stromal modifying moiety, the tumor targeting moiety, or any combination thereof is linked to the first polypeptide, the second polypeptide, the third polypeptide, the fourth polypeptide, or any combination thereof.

[0099] In some embodiments, the immune cell engager, the cytokine molecule, the modulator of a cytokine molecule, the stromal modifying moiety, the tumor targeting moiety, or any combination thereof is within a single contiguous polypeptide chain of the first polypeptide, the second polypeptide, the third cytokine polypeptide, or the fourth cytokine polypeptide to which the immune cell engager, the cytokine molecule, the modulator of a cytokine molecule, the stromal modifying moiety, the tumor targeting moiety, or any combination thereof is linked.

[0100] In some embodiments, the immune cell engager, the cytokine molecule, the modulator of a cytokine molecule, the stromal modifying moiety, the tumor targeting moiety, or any combination thereof is linked to the first polypeptide, the second polypeptide, the third cytokine polypeptide, or the fourth cytokine polypeptide by a linker.

[0101] In some embodiments, the immune cell engager is: the T cell engager, wherein the T cell engager binds to any one selected from the group consisting of CD3, TCRa, TCR[3, TCRy, TCR^, ICOS, CD28, CD27, HVEM, LIGHT, CD40, 4- IBB, 0X40, DR3, GITR, CD30, TIM1, SLAM, CD2, CD226, and any combination thereof; the NK cell engager, wherein the NK cell engager is an antigen binding domain or a ligand that binds to any one selected from the group consisting of NKp30, NKp40, NKp44, NKp46, NKG2D, DNAM1, DAP10, CD16, CRTAM, CD27, PSGL1, CD96, CD100, NKp80, CD244, SLAML6, SLAML7, KIR2DS2, KIR2DS4, KIR3DS1, KIR2DS3, KIR2DS5, KIR2DS1, CD94, NKG2C, NKG2E, CD 160, and any combination thereof; the B cell engager, wherein the B cell engage is selected from the group consisting of CD40L, OX40L, a CD70 ligand, an 0X40 antibody molecule, a CD40 antibody molecule, a CD70 antibody molecule, and any combination thereof; the macrophage cell engager, wherein the macrophage cell engager is selected from the group consisting of a CD2 agonist, CD40L, OX40L, the 0X40 antibody molecule, the CD40 antibody molecule, the CD70 antibody molecule, a Toll-like receptor agonist or fragment thereof, CD47, a STING agonist, and any combination thereof; or the dendritic cell engager, wherein the dendritic cell engager is selected from the group consisting of the CD2 agonist, the 0X40 antibody, the OX40L, a 4 IBB agonist, the Toll-like receptor agonist or the fragment thereof, a CD47 agonist, the STING agonist, and any combination thereof.

[0102] In some embodiments, the cytokine molecule is selected from the group consisting of interleukin- 2 (IL-2) or functional fragment or functional variant thereof, interleukin-7 (IL-7) or functional fragment or functional variant thereof, interleukin- 12 (IL- 12) or functional fragment or functional variant thereof, interleukin- 15 (IL- 15) or functional fragment or functional variant thereof, interleukin- 18 (IL- 18) or functional fragment or functional variant thereof, interleukin -21 (IL-21) or functional fragment orfunctional variant thereof, interferon gamma or functional fragment or functional variant thereof, and any combination thereof.

[0103] In some embodiments, the modulator of a cytokine molecule is a TGF-beta inhibitor.

[0104] In some embodiments, the TGF-beta inhibitor comprises an amino acid sequence with at least 70% sequence identity to any one sequence selected from the group consisting of the extracellular domain sequences of SEQ ID NOs: 93-99, 106, 107, 117-119, 120-126, and 200.

[0105] In some embodiments, the TGF-beta inhibitor comprises an amino acid sequence of any one of the extracellular domain sequences of SEQ ID NOs: 93-99, 106, 107, 117-119, 120-126, and 200.

[0106] In some embodiments, the TGF-beta inhibitor comprises an amino acid sequence with at least 70% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 100-105 and 108.

[0107] In some embodiments, the TGF-beta inhibitor comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 100-105 and 108.

[0108] In some embodiments, the multifunctional molecule comprises an amino acid sequence with at least 70% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 192-199.

[0109] In some embodiments, the multifunctional molecule comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 192-199.

[0110] In some embodiments, the TGF-beta inhibitor targets the bone marrow stromal niche when administered to a subject.

[0111] In some embodiments, the TGF-beta inhibitor targets a malignant haematopoietic stem cell or a progenitor cell in the bone marrow stromal niche when administered to a subject.

[0112] In some embodiments, the tumor targeting moiety binds to any one selected from the group consisting of CD41, P-selectin, Clec2, cKIT, FLT3, MPL, ITGB3, ITGB2, GP5, GP6, GP9, GP1BA, DSC2, FCGR2A, TNFRSF10A, TNFRSF10B, or TM4SF1, alphafetoprotein (AFP), carcinoembryonic antigen (CEA), CA-125, MUC-1, epithelial tumor antigen (ETA), tyrosinase, melanoma-associated antigen (MAGE), HER2, B-cell maturation antigen (BCMA), mesothelin, CD 19, and any combination thereof.

[0113] In some embodiments, the stromal modifying moiety comprises an enzyme molecule that degrades a tumor stroma or extracellular matrix (ECM).

[0114] In some embodiments, the enzyme molecule is selected from the group consisting of a hyaluronidase molecule or variant thereof, a collagenase molecule or variant thereof, a chondroitinase molecule or variant thereof, a matrix metalloproteinase molecule or variant thereof, and any combination thereof.

[0115] In some embodiments, the stromal modifying moiety comprises the hyaluronidase molecule or variant thereof, and wherein the hyaluronidase molecule is selected from the group consisting of hyaluronidase- 1 (HYAL1) or variant thereof, hyaluronidase -2 (HYAL2) or variant thereof, and hyaluronidase PH-20 (PH-20 / SPAM1) or variant thereof.

[0116] In some embodiments, the HYAL1 or variant thereof comprises a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 67.

[0117] In some embodiments, the PH-20 / SPAM1 or variant thereof comprises a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 66.

[0118] In some embodiments, the stromal modifying moiety comprises a hyaluronan degrading enzyme, an agent that inhibits hyaluronan synthesis, an antibody molecule against hyaluronic acid, or any combination thereof.

[0119] In some embodiments, the agent that inhibits hyaluronan synthesis comprises a sense or an antisense nucleic acid molecule against a HA synthase, a small molecule drug, or any combination thereof.

[0120] In some embodiments, the collagenase molecule or variant thereof is collagenase molecule IV or variant thereof.

[0121] In some embodiments, the collagenase molecule IV comprises a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 68.

[0122] In some embodiments, the linker is selected from the group consisting of a cleavable linker, a non- cleavable linker, a peptide linker, a flexible linker, a rigid linker, a helical linker, and a non-helical linker.

[0123] In some embodiments, the linker is the peptide linker comprising any one of the sequences selected from the group consisting of SEQ ID NOs: 69-72, 295, and 296.

[0124] In another aspect, provided herein a pharmaceutical composition comprising the composition as provided herein, and a pharmaceutically acceptable carrier, excipient, or stabilizer.

[0125] In another aspect, provided herein a method of treating a condition or disease in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the composition as provided herein or the pharmaceutical composition as provided herein, wherein the administering is effective to treat the condition or disease in the subject.

[0126] In some embodiments, the condition or disease is cancer.

[0127] In some embodiments, the cancer is a solid cancer.

[0128] In some embodiments, the solid cancer is ovarian cancer, rectal cancer, stomach cancer, testicular cancer, cancer of the anal region, uterine cancer, colon cancer, renal-cell carcinoma, liver cancer, lung cancer, small intestine cancer, esophagus cancer, melanoma, Kaposi's sarcoma, cancer of the endocrine system, thyroid gland cancer, parathyroid gland cancer, adrenal gland cancer, bone cancer, pancreatic cancer, skin cancer, head cancer, neck cancer, brain stem glioma, pituitary adenoma, epidermoid cancer, cervix squamous cell cancer, fallopian tube carcinoma, endometrium carcinoma, vagina cancer, soft tissue sarcoma, urethra cancer, ureter cancer, vulva carcinoma, penis cancer, breast cancer, bladder cancer, kidney cancer, renal pelvis cancer, spinal axis tumor, central nervous system (CNS) neoplasm, primary CNS lymphoma, tumor angiogenesis, cancer of metastatic lesions, or any combination thereof.

[0129] In some embodiments, the lung cancer is small cell lung cancer, or non-small cell lung cancer.

[0130] In some embodiments, the melanoma is cutaneous malignant melanoma, or intraocular malignant melanoma.

[0131] In some embodiments, the pancreatic cancer is pancreatic adenocarcinoma.

[0132] In some embodiments, the cancer is a myeloproliferative neoplasm.

[0133] In some embodiments, the myeloproliferative neoplasm is primary or idiopathic myelofibrosis (MF), essential thrombocythemia or thrombocytosis (ET), polycythemia vera (PV), chronic myelogenous leukemia (CML), or myelofibrosis.

[0134] In some embodiments, the cancer is essential thrombocythemia or thrombocytosis (ET), and the subject also has secondary myelofibrosis.

[0135] In some embodiments, the cancer is polycythemia vera (PV), and the subject also has secondary myelofibrosis.

[0136] In some embodiments, the cancer is a hematological cancer.

[0137] In some embodiments, the hematological cancer is a leukemia or a lymphoma,

[0138] In some embodiments, the leukemia is acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), hairy cell leukemia, acute monocytic leukemia (AMoL), chronic myelomonocytic leukemia (CMML), juvenile myelomonocytic leukemia (JMML), or large granular lymphocytic leukemia.

[0139] In some embodiments, the lymphoma is AIDS-related lymphoma, cutaneous T-cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, chronic myeloproliferative neoplasm, Langerhans cell histiocytosis, multiple myeloma / plasma cell neoplasm, myelodysplastic syndrome, myelodysplastic neoplasm, primary central nervous system lymphoma, or myeloproliferative neoplasm.

[0140] In some embodiments, the Hodgkin lymphoma is classical Hodgkin lymphoma, or nodular lymphocyte-predominant Hodgkin lymphoma.

[0141] In some embodiments, the non-Hodgkin lymphoma is B-cell non-Hodgkin lymphoma, or T-cell non-Hodgkin lymphoma.

[0142] In some embodiments, B-cell non-Hodgkin lymphoma is Burkitt lymphoma, small lymphocytic lymphoma (CLL / SLL), diffuse large B-cell lymphoma, follicular lymphoma, immunoblastic large cell lymphoma, precursor B -lymphoblastic lymphoma, mantle cell lymphoma, or Waldenstrom macroglobulinemia.

[0143] In some embodiments, T-cell non-Hodgkin lymphoma is mycosis fungoides, anaplastic large cell lymphoma, Sezary syndrome, or precursor T-lymphoblastic lymphoma.

[0144] In some embodiments, the subject is human.

[0145] In some embodiments, the method as provided herein further comprises administering a second therapeutic agent or therapy to the subject.

[0146] In some embodiments, the second therapeutic agent or therapy comprises a chemotherapeutic agent, a biologic agent, a viral cancer therapeutic agent, an RNAi agent, an antisense RNA agent, a hormonal therapy, radiation, surgery, or any combination thereof.

[0147] In some embodiments, the second therapeutic agent or therapy is administered in combination with the composition as provided herein or the pharmaceutical composition as provided herein previously, concurrently, or sequentially.

[0148] In another aspect, provided herein a method of targeting a TGF-beta inhibitor to a bone marrowstromal niche in a subject, the method comprises administering the composition as provided herein to a subject in need thereof, wherein the TCF-beta inhibitor is targeted to the bone marrow stromal niche in the subject.

[0149] In some embodiments, the TGF-beta inhibitor is targeted to a malignant haematopoietic stem cell or a progenitor cell in the bone marrow stromal niche in the subject.BRIEF DESCRIPTION OF THE DRAWINGS

[0150] FIGs. 1A-1C are schematic representations of exemplary formats and configurations of functional moieties attached to a dimerization module (e.g., an immunoglobulin constant domain). FIG. 1A depicts moieties A, B, C and D, covalently linked to a heterodimeric Fc domain. FIG. IB depicts moieties A, B, C and D, covalently linked to a homodimeric Fc domain. FIG. 1C depicts moieties A, B, C and D, covalently linked to heterodimeric heavy and light constant domains (e.g., a Fab CHI and a Fab CL). In some embodiments, the functional moiety is a first tumor-targeting moiety that binds to a first tumor antigen. In some embodiments, the functional moiety is a second tumor-targeting moiety that binds to a second tumor antigen. In some embodiments, the functional moiety is a third tumor-targeting moiety that binds to a second tumor antigen. In some embodiments, the first, second, and optionally the third tumor antigens are each independently selected from the group consisting of CD34 and G6B. In some embodiments, the functional moiety is an immune cell engager selected from the group consisting of a T cell engager, an NK cell engager, a B cell engager, a dendritic cell engager, and a macrophage cell engager. In some embodiments, the functional moiety is a cytokine molecule. In some embodiments, the functional moiety is a modulator of a cytokine molecule. In some embodiments, the functional moiety is a stromal modifying moiety. In some embodiments, the functional moiety is a modulator of a cytokine molecule. In some embodiments, the functional moiety is a TGF-beta inhibitor.

[0151] FIGs. 2A-2L are schematics showing exemplary multispecific molecules comprising a binding moiety A, binding moiety B, functional moiety A, and functional moiety B. In some embodiments, binding moiety A and binding moiety B independently comprises an anti-CD34 antibody or binding fragment thereof or anti- G6B antibody or binding fragment thereof. In some embodiments, an anti-CD34 antibody or binding fragment thereof or anti- G6B antibody or binding fragment thereof is independently a full-length antibody, a Fab, a F(ab')2, an Fv, a single chain Fv, a single domain antibody, a half arm antibody, a diabody (dAb), a bivalent antibody, a monovalent antibody, a bispecific antibody or fragment thereof, or a camelid antibody. In some embodiments, functional moiety A and functional moiety B are independently an antigen binding moiety, an immune cell engager, a cytokine molecule, a modulator of a cytokine molecule, a stromal modifying moiety, or any combination thereof. In some embodiment, functional moiety A and functional moiety B are independently an immune cell engager selected from the group consisting of a T cell engager, an NK cell engager, a B cell engager, a dendritic cell engager, and a macrophage cell engager. In some embodiments, the functional moiety is a stromal modifying moiety. In some embodiments, functional moiety A, functional moiety B, or any combination thereof is a modulator of a cytokine molecule. In some embodiments, functional moiety A, functional moiety B, or any combination thereof is a TGF-beta inhibitor.

[0152] FIG. 2A shows an exemplary embodiment of a multifunctional molecule that comprises binding moiety A and binding moiety B, which are independently a Fab of an anti-CD34 antibody and a Fab of anti- G6B antibody, linked to the N-terminus of two Fc regions, and functional moiety A and functional moiety B, which are independently an antigen binding moiety, an immune cell engager, a cytokine molecule, a modulator of a cytokine molecule, a stromal modifying moiety, or any combination thereof, linked to the C- terminus of two Fc regions. FIG. 2B shows an exemplary embodiment of a multifunctional molecule that comprises binding moiety A and binding moiety B, which are independently a Fab of an anti-CD34 antibody and a Fab of anti- G6B antibody, linked to the N-terminus and C-terminus of a first Fc region, respectively, and functional moiety A and functional moiety B, which are independently an antigen binding moiety, an immune cell engager, a cytokine molecule, a modulator of a cytokine molecule, a stromal modifying moiety, or any combination thereof, linked to the N-terminus and C-terminus of a second Fc region, respectively. FIG. 2C shows an exemplary embodiment of a multifunctional molecule that comprises binding moiety A and binding moiety B, which are independently a Fab of an anti-CD34 antibody and a Fab of anti- G6B antibody, linked to the N-terminus of a first Fc region and the C-terminus of a second Fc region, respectively, and functional moiety A and functional moiety B, which are independently an antigen binding moiety, an immune cell engager, a cytokine molecule, a modulator of a cytokine molecule, a stromal modifying moiety, or any combination thereof, linked to the C-terminus of a first Fc region and the N- terminus of a second Fc region, respectively. FIG. 2D shows an exemplary embodiment of a multifunctional molecule that comprises binding moiety A and binding moiety B, which are independently a Fab of an anti- CD34 antibody and a Fab of anti- G6B antibody, linked to the C-terminus of two Fc regions, and functional moiety A and functional moiety B, which are independently an antigen binding moiety, an immune cell engager, a cytokine molecule, a modulator of a cytokine molecule, a stromal modifying moiety, or any combination thereof, linked to the N-terminus of two Fc regions.

[0153] FIG. 2E shows an exemplary embodiment of a multifunctional molecule that comprises binding moiety A and binding moiety B, which are independently a Fab of an anti-CD34 antibody and an scFv of anti- G6B antibody or an scFv of an anti-CD34 antibody and a Fab of anti- G6B antibody, linked to the N- terminus of two Fc regions, and functional moiety A and functional moiety B, which are independently an antigen binding moiety, an immune cell engager, a cytokine molecule, a modulator of a cytokine molecule, a stromal modifying moiety, or any combination thereof, linked to the C-terminus of two Fc regions. FIG. 2F shows an exemplary embodiment of a multifunctional molecule that comprises binding moiety A and binding moiety B, which are independently a Fab of an anti-CD34 antibody and an scFv of anti- G6B antibody or an scFv of an anti-CD34 antibody and a Fab of anti- G6B antibody, linked to the N-terminus and C-terminus of a first Fc region, respectively, and functional moiety A and functional moiety B, which are independently an antigen binding moiety, an immune cell engager, a cytokine molecule, a modulator of a cytokine molecule, a stromal modifying moiety, or any combination thereof, linked to the N-terminus and C- terminus of a second Fc region, respectively. FIG. 2G shows an exemplary embodiment of a multifunctional molecule that comprises binding moiety A and binding moiety B, which are independently a Fab of an anti-CD34 antibody and an scFv of anti- G6B antibody or an scFv of an anti-CD34 antibody and a Fab of anti- G6B antibody, linked to the N-terminus of a first Fc region and the C-terminus of a second Fc region, respectively, and functional moiety A and functional moiety B, which are independently an antigen binding moiety, an immune cell engager, a cytokine molecule, a modulator of a cytokine molecule, a stromal modifying moiety, or any combination thereof, linked to the C-terminus of a first Fc region and the N- terminus of a second Fc region, respectively. FIG. 2H shows an exemplary embodiment of a multifunctional molecule that comprises binding moiety A and binding moiety B, which are independently a Fab of an anti- CD34 antibody and an scFv of anti- G6B antibody or an scFv of an anti-CD34 antibody and a Fab of anti- G6B antibody, linked to the C-terminus of two Fc regions, and functional moiety A and functional moiety B, which are independently an antigen binding moiety, an immune cell engager, a cytokine molecule, a modulator of a cytokine molecule, a stromal modifying moiety, or any combination thereof, linked to the N- terminus of two Fc regions.

[0154] FIG. 21 shows an exemplary embodiment of a multifunctional molecule that comprises binding moiety A and binding moiety B, which are independently an scFv of an anti-CD34 antibody and an scFv of anti- G6B antibody, linked to the N-terminus of two Fc regions, and functional moiety A and functional moiety B, which are independently an antigen binding moiety, an immune cell engager, a cytokine molecule, a modulator of a cytokine molecule, a stromal modifying moiety, or any combination thereof, linked to the C-terminus of two Fc regions. FIG. 2 J shows an exemplary embodiment of a multifunctional molecule that comprises binding moiety A and binding moiety B, which are independently an scFv of an anti-CD34 antibody and an scFv of anti- G6B antibody, linked to the N-terminus and C-terminus of a first Fc region, respectively, and functional moiety A and functional moiety B, which are independently an antigen binding moiety, an immune cell engager, a cytokine molecule, a modulator of a cytokine molecule, a stromal modifying moiety, or any combination thereof, linked to the N-terminus and C-terminus of a second Fc region, respectively. FIG. 2K shows an exemplary embodiment of a multifunctional molecule that comprises binding moiety A and binding moiety B, which are independently an scFv of an anti-CD34 antibody and an scFv of anti- G6B antibody, linked to the N-terminus of a first Fc region and the C-terminus of a second Fc region, respectively, and functional moiety A and functional moiety B, which are independently an antigen binding moiety, an immune cell engager, a cytokine molecule, a modulator of a cytokine molecule, a stromal modifying moiety, or any combination thereof, linked to the C-terminus of a first Fc region and the N- terminus of a second Fc region, respectively. FIG. 2L shows an exemplary embodiment of a multifunctional molecule that comprises binding moiety A and binding moiety B, which are independently an scFv of an anti-CD34 antibody and an scFv of anti- G6B antibody, linked to the C-terminus of two Fc regions, and functional moiety A and functional moiety B, which are independently an antigen binding moiety, an immune cell engager, a cytokine molecule, a modulator of a cytokine molecule, a stromal modifying moiety, or any combination thereof, linked to the N-terminus of two Fc regions.DETAILED DESCRIPTION OF THE INVENTIONDEFINITIONS

[0155] Certain specific details of this description are set forth in order to provide a thorough understanding of various embodiments. However, one skilled in the art will understand that the present disclosure may be practiced without these details. In other instances, well-known structures have not been shown or described in detail to avoid unnecessarily obscuring descriptions of the embodiments.

[0156] Unless the context requires otherwise, throughout the specification and claims which follow, the word “comprise” and variations thereof, such as, “comprises” and “comprising” are to be construed in an open, inclusive sense, that is, as “including, but not limited to.” Further, headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed disclosure.

[0157] As used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the content clearly dictates otherwise. The use of the words “a” or “an” when used in conjunction with the term “comprising” herein may mean “one,” but it is also consistent with the meaning of “one or more,” “at least one,” and “one or more than one.”

[0158] It should also be noted that the term “or” is generally employed in its sense including “and / or” unless the content clearly dictates otherwise.

[0159] The term “about” when referring to a measurable value such as an amount, a temporal duration, and the like, is meant to encompass variations of ±20% or in some instances ±10%, or in some instances ±5%, or in some instances ±1%, or in some instances ±0.1% from the specified value, as such variations are appropriate to perform the disclosed methods. As used herein, “about” and “approximately” generally mean an acceptable degree of error for the quantity measured given the nature or precision of the measurements. Exemplary degrees of error are within 20 percent (%), typically, within 10%, and more typically, within 5% of a given range of values.

[0160] The term “acquire” or “acquiring” as the terms are used herein, refer to obtaining possession of a physical entity (e.g., a sample, a polypeptide, a nucleic acid, or a sequence), or a value, e.g., a numerical value, by “directly acquiring” or “indirectly acquiring” the physical entity or value. “Directly acquiring” means performing a process (e.g., performing a synthetic or analytical method) to obtain the physical entity or value. “Indirectly acquiring” refers to receiving the physical entity or value from another party or source (e.g., a third party laboratory that directly acquired the physical entity or value). Directly acquiring a physical entity includes performing a process that includes a physical change in a physical substance, e.g., a starting material. Directly acquiring a value includes performing a process that includes a physical change in a sample or another substance, e.g., performing an analytical process which includes a physical change in a substance, e.g., a sample.

[0161] “Antibody molecule” as used herein refers to a protein, e.g., an immunoglobulin chain or fragment thereof, comprising at least one immunoglobulin variable domain structure and / or sequence. An antibody molecule encompasses antibodies (e.g., full-length antibodies) and antibody fragments. In some embodiments, an antibody molecule comprises an antigen binding or functional fragment of a full lengthantibody, or a full length immunoglobulin chain. For example, a full-length antibody is an immunoglobulin (Ig) molecule (e.g., an IgG antibody) that is naturally occurring or formed by normal immunoglobulin gene fragment recombinatorial processes). In some embodiments, an antibody molecule refers to an immunologically active, antigen-binding portion of an immunoglobulin molecule, such as an antibody fragment. An antibody fragment, e.g., functional fragment, is a portion of an antibody, e.g., Fab, Fab', F(ab')2, F(ab)2, variable fragment (Fv), domain antibody (dAb), or single chain variable fragment (scFv). A functional antibody fragment binds to the same antigen as that recognized by the intact (e.g., full-length) antibody. The terms “antibody fragment” or “functional fragment” also include isolated fragments consisting of the variable regions, such as the “Fv” fragments consisting of the variable regions of the heavy and light chains or recombinant single chain polypeptide molecules in which light and heavy variable regions are connected by a peptide linker (“scFv proteins”). In some embodiments, an antibody fragment does not include portions of antibodies without antigen binding activity, such as Fc fragments or single amino acid residues. Exemplary antibody molecules include full length antibodies and antibody fragments, e.g., dAb (domain antibody), single chain, Fab, Fab’, and F(ab’)2 fragments, and single chain variable fragments (scFvs). In some embodiments, the antibody molecule is an antibody mimetic. In some embodiments, the antibody molecule is, or comprises, an antibody-like framework or scaffold, such as, fibronectins, ankyrin repeats (e.g., designed ankyrin repeat proteins (DARPins)), avimers, affibody affinity ligands, anticalins, or affilin molecules.

[0162] The term “human-like antibody molecule” as used herein refers to a humanized antibody molecule, human antibody molecule or an antibody molecule having at least 95% sequence identity with a non-murine germline framework region, e.g., FR1, FR2, FR3 and / or FR4. In some embodiments, the human-like antibody molecule comprises a framework region having at least 95% sequence identity to a human germline framework region, e.g., a FR1, FR2, FR3 and / or FR4 of a human germline framework region. In some embodiments, the human-like antibody molecule is a recombinant antibody. In some embodiments, the human-like antibody molecule is a humanized antibody molecule. In some embodiments, the human-like antibody molecule is human antibody molecule. In some embodiments, the human-like antibody molecule is a phage display or a yeast display antibody molecule. In some embodiments, the human-like antibody molecule is a chimeric antibody molecule. In some embodiments, the human-like antibody molecule is a CDR grafted antibody molecule.

[0163] As used herein, an “immunoglobulin variable domain sequence” refers to an amino acid sequence which can form the structure of an immunoglobulin variable domain. For example, the sequence may include all or part of the amino acid sequence of a naturally-occurring variable domain. For example, the sequence may or may not include one, two, or more N- or C-terminal amino acids, or may include other alterations that are compatible with formation of the protein structure.

[0164] In some embodiments, an antibody molecule is monospecific, e.g., it comprises binding specificity for a single epitope. In some embodiments, an antibody molecule is multispecific, e.g., it comprises a plurality of immunoglobulin variable domain sequences, where a first immunoglobulin variable domainsequence has binding specificity for a first epitope and a second immunoglobulin variable domain sequence has binding specificity for a second epitope. In some embodiments, an antibody molecule is a bispecific antibody molecule. “Bispecific antibody molecule” as used herein refers to an antibody molecule that has specificity for more than one (e.g., two, three, four, or more) epitope and / or antigen.

[0165] “Antigen” (Ag) as used herein refers to a molecule that can provoke an immune response, e.g., involving activation of certain immune cells and / or antibody generation. Any macromolecule, including almost all proteins or peptides, can be an antigen. Antigens can also be derived from genomic recombinant or DNA. For example, any DNA comprising a nucleotide sequence or a partial nucleotide sequence that encodes a protein capable of eliciting an immune response encodes an “antigen.” In some embodiments, an antigen does not need to be encoded solely by a full length nucleotide sequence of a gene, nor does an antigen need to be encoded by a gene at all. In some embodiments, an antigen can be synthesized or can be derived from a biological sample, e.g., a tissue sample, a tumor sample, a cell, or a fluid with other biological components. As used, herein a “tumor antigen” or interchangeably, a “cancer antigen” includes any molecule present on, or associated with, a cancer, e.g., a cancer cell or a tumor microenvironment that can provoke an immune response. As used, herein an “immune cell antigen” includes any molecule present on, or associated with, an immune cell that can provoke an immune response.

[0166] The “antigen-binding site,” or “binding portion” of an antibody molecule refers to the part of an antibody molecule, e.g., an immunoglobulin (Ig) molecule, that participates in antigen binding. In some embodiments, the antigen binding site is formed by amino acid residues of the variable (V) regions of the heavy (H) and light (L) chains. Three highly divergent stretches within the variable regions of the heavy and light chains, referred to as hypervariable regions, are disposed between more conserved flanking stretches called “framework regions,” (FRs). FRs are amino acid sequences that are naturally found between, and adjacent to, hypervariable regions in immunoglobulins. In some embodiments, in an antibody molecule, the three hypervariable regions of a light chain and the three hypervariable regions of a heavy chain are disposed relative to each other in three dimensional space to form an antigen-binding surface, which is complementary to the three-dimensional surface of a bound antigen. The three hypervariable regions of each of the heavy and light chains are referred to as “complementarity-determining regions,” or “CDRs.” The framework region and CDRs have been defined and described, e.g., in Kabat, E.A., et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No. 91-3242, and Chothia, C. et al. (1987) J. Mol. Biol. 196:901-917. Each variable chain (e.g., variable heavy chain and variable light chain) is typically made up of three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the amino acid order: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4.

[0167] As used herein, an “immune cell” refers to any of various cells that function in the immune system, e.g., to protect against agents of infection and foreign matter. In some embodiments, this term includes leukocytes, e.g., neutrophils, eosinophils, basophils, lymphocytes, and monocytes. Innate leukocytes include phagocytes (e.g., macrophages, neutrophils, and dendritic cells), mast cells, eosinophils,basophils, and natural killer cells. Innate leukocytes identify and eliminate pathogens, either by attacking larger pathogens through contact or by engulfing and then killing microorganisms, and are mediators in the activation of an adaptive immune response. The cells of the adaptive immune system are special types of leukocytes, called lymphocytes. B cells and T cells are important types of lymphocytes and are derived from hematopoietic stem cells in the bone marrow. B cells are involved in the humoral immune response, whereas T cells are involved in cell-mediated immune response. The term “immune cell” includes immune effector cells.

[0168] As used herein, the term “immune effector cell” refers to a cell that is involved in an immune response, e.g., in the promotion of an immune effector response. Examples of immune effector cells include, but are not limited to, T cells, e.g., alpha / beta T cells and gamma / delta T cells, B cells, natural killer (NK) cells, natural killer T (NK T) cells, and mast cells.

[0169] The term “effector function” or “effector response” refers to a specialized function of a cell. Effector function of a T cell, for example, may be cytolytic activity or helper activity including the secretion of cytokines.

[0170] The terms “polypeptide”, “peptide” and “protein” (if single chain) are used interchangeably herein to refer to polymers of amino acids of any length. The polymer may be linear or branched, it may comprise modified amino acids, and it may be interrupted by non-amino acids. The terms also encompass an amino acid polymer that has been modified; for example, disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other manipulation, such as conjugation with a labeling component. The polypeptide can be isolated from natural sources, can be a produced by recombinant techniques from a eukaryotic or prokaryotic host, or can be a product of synthetic procedures.

[0171] The terms “nucleic acid,” “nucleic acid sequence,” “nucleotide sequence,” or “polynucleotide sequence,” and “polynucleotide” are used interchangeably. They refer to a polymeric form of nucleotides of any length, either deoxyribonucleotides or ribonucleotides, or analogs thereof. The polynucleotide may be either single -stranded or double-stranded, and if single-stranded may be the coding strand or non-coding (antisense) strand. A polynucleotide may comprise modified nucleotides, such as methylated nucleotides and nucleotide analogs. The sequence of nucleotides may be interrupted by non-nucleotide components. A polynucleotide may be further modified after polymerization, such as by conjugation with a labeling component. The nucleic acid may be a recombinant polynucleotide, or a polynucleotide of genomic, cDNA, semisynthetic, or synthetic origin which either does not occur in nature or is linked to another polynucleotide in a non-natural arrangement.

[0172] The term “isolated,” as used herein, refers to material that is removed from its original or native environment (e.g., the natural environment if it is naturally occurring). For example, a naturally-occurring polynucleotide or polypeptide present in a living animal is not isolated, but the same polynucleotide or polypeptide, separated by human intervention from some or all of the co-existing materials in the natural system, is isolated. Such polynucleotides could be part of a vector and / or such polynucleotides or polypeptides could be part of a composition, and still be isolated in that such vector or composition is notpart of the environment in which it is found in nature. An isolated polynucleotide (ribonucleic acid (RNA), deoxyribonucleic acid (DNA)), or polypeptide is free of the genes / nucleic acids or sequences / amino acids that flank it in its naturally-occurring state.

[0173] The compositions and methods of the present invention encompass polypeptides and nucleic acids having the sequences specified, or sequences substantially identical or similar thereto, e.g., sequences at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% identical or higher to the sequence specified. In the context of an amino acid sequence, the term “substantially identical” is used herein to refer to a first amino acid that contains a sufficient or minimum number of amino acid residues that are i) identical to, or ii) conservative substitutions of aligned amino acid residues in a second amino acid sequence such that the first and second amino acid sequences can have a common structural domain and / or common functional activity. For example, amino acid sequences that contain a common structural domain having at least about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%. 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% 99%, 99.5%, 99.9%, or 100% sequence identity to a reference sequence, e.g., a sequence provided herein.

[0174] In the context of nucleotide sequence, the term “substantially identical” is used herein to refer to a first nucleic acid sequence that contains a sufficient or minimum number of nucleotides that are identical to aligned nucleotides in a second nucleic acid sequence such that the first and second nucleotide sequences encode a polypeptide having common functional activity, or encode a common structural polypeptide domain or a common functional polypeptide activity. For example, nucleotide sequences having at least about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% 99%, 99.5%, 99.9%, or 100% sequence identity to a reference sequence, e.g., a sequence provided herein.

[0175] The term “variant” refers to a polypeptide that has a substantially identical amino acid sequence to a reference amino acid sequence, or is encoded by a substantially identical nucleotide sequence. In some embodiments, the variant is a functional variant.

[0176] The term “functional variant” refers to a polypeptide that has a substantially identical amino acid sequence to a reference amino acid sequence, or is encoded by a substantially identical nucleotide sequence, and is capable of having one or more activities of the reference amino acid sequence.

[0177] Calculations of homology or sequence identity between sequences (the terms are used interchangeably herein) are performed as follows. To determine the percent identity of two amino acid sequences, or of two nucleic acid sequences, the sequences are aligned for optimal comparison purposes (e.g., gaps can be introduced in one or both of a first and a second amino acid or nucleic acid sequence for optimal alignment and non-homologous sequences can be disregarded for comparison purposes). In a preferred embodiment, the length of a reference sequence aligned for comparison purposes is at least 30%, preferably at least 40%, more preferably at least 50%, 60%, and even more preferably at least 70%, 80%, 90%, 100% of the length of the reference sequence. The amino acid residues or nucleotides at corresponding amino acid positions or nucleotide positions are then compared. When a position in the first sequence is occupied by the same amino acid residue or nucleotide as the corresponding position in the second sequence, then the molecules are identical at that position (as used herein amino acid or nucleic acid “identity” isequivalent to amino acid or nucleic acid “homology”).

[0178] The percent identity between the two sequences is a function of the number of identical positions shared by the sequences, taking into account the number of gaps, and the length of each gap, which need to be introduced for optimal alignment of the two sequences. The comparison of sequences and determination of percent identity between two sequences can be accomplished using a mathematical algorithm. In a preferred embodiment, the percent identity between two amino acid sequences is determined using the Needleman and Wunsch ((1970) J. Mol. Biol. 48:444-453 ) algorithm which has been incorporated into the GAP program in the GCG software package (available at http: / / www.gcg.com), using either a Blossum 62 matrix or a PAM250 matrix, and a gap weight of 16, 14, 12, 10, 8, 6, or 4 and a length weight of 1, 2, 3, 4, 5, or 6. In yet another preferred embodiment, the percent identity between two nucleotide sequences is determined using the GAP program in the GCG software package (available at http: / / www.gcg.com), using a NWSgapdna.CMP matrix and a gap weight of 40, 50, 60, 70, or 80 and a length weight of 1, 2, 3, 4, 5, or 6. A particularly preferred set of parameters (and the one that should be used unless otherwise specified) are a Blossum 62 scoring matrix with a gap penalty of 12, a gap extend penalty of 4, and a frameshift gap penalty of 5.

[0179] The percent identity between two amino acid or nucleotide sequences can be determined using the algorithm of E. Meyers and W. Miller ((1989) CABIOS, 4: 11-17) which has been incorporated into the ALIGN program (version 2.0), using a PAM120 weight residue table, a gap length penalty of 12 and a gap penalty of 4. The nucleic acid and protein sequences described herein can be used as a “query sequence” to perform a search against public databases to, for example, identify other family members or related sequences. Such searches can be performed using the NBLAST and XBLAST programs (version 2.0) of Altschul, et al. (1990) J. Mol. Biol. 215:403-10. BLAST nucleotide searches can be performed with the NBLAST program, score = 100, wordlength = 12 to obtain nucleotide sequences homologous to a nucleic acid molecule of the invention. BLAST protein searches can be performed with the XBLAST program, score = 50, wordlength = 3 to obtain amino acid sequences homologous to protein molecules of the invention. To obtain gapped alignments for comparison purposes, Gapped BLAST can be utilized as described in Altschul et al., (1997) Nucleic Acids Res. 25:3389-3402. When utilizing BLAST and Gapped BLAST programs, the default parameters of the respective programs (e.g., XBLAST and NBLAST) can be used.

[0180] It is understood that the molecules of the present invention may have additional conservative or non-essential amino acid substitutions, which do not have a substantial effect on their functions.

[0181] The term “amino acid” is intended to embrace all molecules, whether natural or synthetic, which include both an amino functionality and an acid functionality and capable of being included in a polymer of naturally-occurring amino acids. Exemplary amino acids include naturally-occurring amino acids; analogs, derivatives and congeners thereof; amino acid analogs having variant side chains; and all stereoisomers of any of any of the foregoing. As used herein the term “amino acid” includes both the D- or L- optical isomers and peptidomimetics.

[0182] As used herein, a “conservative amino acid substitution” is one in which the amino acid residue is replaced with an amino acid residue having a similar side chain. Families of amino acid residues having similar side chains have been defined in the art. These families include amino acids with basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), beta-branched side chains (e.g., threonine, valine, isoleucine) and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine).

[0183] As used herein, the term “molecule” as used in, e.g., antibody molecule, cytokine molecule, receptor molecule, includes full-length, naturally-occurring molecules, as well as variants, e.g., functional variants (e.g., truncations, fragments, mutated (e.g., substantially similar sequences) or derivatized form thereof), so long as at least one function and / or activity of the unmodified (e.g., naturally-occurring) molecule remains.

[0184] As used herein, the term “mutation” refers to an alteration in the nucleotide sequence of the genome of an organism, virus, or extrachromosomal DNA. In some embodiments, the mutation may be a large-scale mutation, such as amplifications (or gene duplications) or repetitions of a chromosomal segment, deletions of large chromosomal regions, chromosomal rearrangements (e.g., chromosomal translocations, chromosomal inversions, non-homologous chromosomal crossover, and interstitial deletions), and loss of heterozygosity. In some embodiments, the mutation may be a small-scale mutation, such as insertions, deletions, and substitution mutations. As used herein, the term “substitution mutation” refers to the transition that exchange a single nucleotide for another.

[0185] As used herein, the term “an immune cell engager” refers to one or more binding specificities that bind and / or activate an immune cell, e.g., a cell involved in an immune response. In some embodiments, the immune cell is selected from the group consisting of a T cell, an NK cell, a B cell, a dendritic cell, a macrophage cell, and any combination thereof. The immune cell engager can be an antibody molecule, a receptor molecule (e.g., a full length receptor, receptor fragment, or fusion thereof (e.g., a receptor-Fc fusion)), or a ligand molecule (e.g., a full length ligand, ligand fragment, or fusion thereof (e.g., a ligand-Fc fusion)) that binds to the immune cell antigen (e.g., the T cell, the NK cell antigen, the B cell antigen, the dendritic cell antigen, and / or the macrophage cell antigen). In some embodiments, the immune cell engager specifically binds to the target immune cell, e.g., binds preferentially to the target immune cell. For example, when the immune cell engager is an antibody molecule, it binds to an immune cell antigen (e.g., a T cell antigen, an NK cell antigen, a B cell antigen, a dendritic cell antigen, and / or a macrophage cell antigen) with a dissociation constant of less than about 10 nM.

[0186] As used herein, the term “a cytokine molecule” refers to full length, a fragment or a variant of a cytokine; a cytokine further comprising a receptor domain, e.g., a cytokine receptor dimerizing domain; or an agonist of a cytokine receptor, e.g., an antibody molecule (e.g., an agonistic antibody) to a cytokine receptor, that elicits at least one activity of a naturally-occurring cytokine. In some embodiments, thecytokine molecule is selected from the group consisting of interleukin-2 (IL-2), interleukin-7 (IL-7), interleukin- 12 (IL-12), interleukin- 15 (IL-15), interleukin- 18 (IL-18), interleukin-21 (IL-21), or interferon gamma, or a fragment or variant thereof, and any combination of any of the aforesaid cytokines. The cytokine molecule can be a monomer or a dimer. In some embodiments, the cytokine molecule can further include a cytokine receptor dimerizing domain. In other embodiments, the cytokine molecule is an agonist of a cytokine receptor, e.g., an antibody molecule (e.g., an agonistic antibody) to a cytokine receptor selected from the group consisting of an IL-15Ra and IL-21R.

[0187] As used herein, the term “a stromal modifying moiety” refers to an agent, e.g., a protein (e.g., an enzyme), that is capable of altering, e.g., degrading a component of, the stroma. In some embodiments, the component of the stroma is selected from, e.g., an ECM component, e.g., a glycosaminoglycan, e.g., hyaluronan (also known as hyaluronic acid or HA), chondroitin sulfate, chondroitin, dermatan sulfate, heparin sulfate, heparin, entactin, tenascin, aggrecan and keratin sulfate; or an extracellular protein, e.g., collagen, laminin, elastin, fibrinogen, fibronectin, and vitronectin.

[0188] The term “G6B” also known as MPIG6B (megakaryocyte and platelet inhibitory receptor G6b), G6b, NG31, C6orf25, chromosome 6 open reading frame 25, G6b-B, megakaryocyte and platelet inhibitory receptor G6b, and THAMY, refers to a protein that is a member of the immunoglobulin (Ig) superfamily and is located in the major histocompatibility complex (MHC) class III region. In some embodiments, G6B protein is a glycosylated, plasma membrane -bound cell surface receptor. G6B, as used herein, includes any of the recombinant or naturally-occurring forms of G6B or variants or homologs thereof that have or maintain G6B activity (e.g., at least 40% 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 100% activity). In some aspects, the variants or homologs have at least 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity across the whole sequence or a portion of the sequence (e.g., a 50, 100, 150 or 200 continuous amino acid portion) compared to a naturally occurring G6B. In some embodiments, G6B is substantially identical to the protein identified by the UniProt reference number 095866 or a variant or homolog having substantial identity thereto. In some embodiments, Swiss-Prot accession number 095866 provides exemplary human G6B amino acid sequences. In some embodiments, G6B or G6B molecule is a naturally-existing G6B or a functional variant or fragment thereof.

[0189] The term “CD34” or “Cluster of Differentiation 34” also known as entrez:947 and CD34 molecule, refers to a transmembrane phosphoglycoprotein protein encoded by the CD34 gene in humans, mice, rats and other species. CD34, as used herein, includes any of the recombinant or naturally-occurring forms of CD34 or variants or homologs thereof that have or maintain CD34 activity (e.g., at least 40% 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 100% activity). In some aspects, the variants or homologs have at least 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity across the whole sequence or a portion of the sequence (e.g., a 50, 100, 150 or 200 continuous amino acid portion) compared to a naturally occurring CD34. In some embodiments, CD34 is substantially identical to the protein identified by the UniProt reference numberP28906 or a variant or homolog having substantial identity thereto. In some embodiments, CD34 refers to hematopoietic progenitor cell antigen CD34. In some embodiments, Swiss-Prot accession number P28906 provides exemplary human CD34 amino acid sequences. In some embodiments, CD34 or CD34 molecule is a naturally-existing CD34 or a functional variant or fragment thereof.

[0190] As used herein, the term “transforming growth factor beta-1 (TGF-beta 1)” refers to a protein that in humans is encoded by the gene TGFB1, or its orthologs. Swiss-Prot accession number P01137 provides exemplary human TGF-beta 1 amino acid sequences. An exemplary immature human TGF-beta 1 amino acid sequence is provided in SEQ ID NO: 200. An exemplary mature human TGF-beta 1 amino acid sequence is provided in SEQ ID NO: 117.

[0191] As used herein, the term “transforming growth factor beta-2 (TGF-beta 2)” refers to a protein that in humans is encoded by the gene TGFB2, or its orthologs. Swiss-Prot accession number P61812 provides exemplary human TGF-beta 2 amino acid sequences. An exemplary immature human TGF-beta 2 amino acid sequence is provided in SEQ ID NO: 93. An exemplary mature human TGF-beta 2 amino acid sequence is provided in SEQ ID NO: 118.

[0192] As used herein, the term “transforming growth factor beta-3 (TGF-beta 3)” refers to a protein that in humans is encoded by the gene TGFB3, or its orthologs. Swiss-Prot accession number P10600 provides exemplary human TGF-beta 3 amino acid sequences. An exemplary immature human TGF-beta 3 amino acid sequence is provided in SEQ ID NO: 94. An exemplary mature human TGF-beta 3 amino acid sequence is provided in SEQ ID NO: 119.

[0193] As used herein, a “TGF-beta receptor polypeptide” refers to a TGF-beta receptor (e.g., TGFBR1, TGFBR2, or TGFBR3) or its fragment, or variant thereof.

[0194] As used herein, the term “transforming growth factor beta receptor type 1 (TGFBR1)” (also known as ALK-5 or SKR4) refers to a protein that in humans is encoded by the gene TGFBR1, or its orthologs. Swiss-Prot accession number P36897 provides exemplary human TGFBR1 amino acid sequences. Exemplary immature human TGFBR1 amino acid sequences are provided in SEQ ID NOs: 95, 96, and 97. Exemplary mature human TGFBR1 amino acid sequences are provided in SEQ ID NOs: 120, 121, and 122. As used herein, a “TGFBR1 polypeptide” refers to a TGFBR1 or its fragment, or variant thereof.

[0195] As used herein, the term “transforming growth factor beta receptor type 2 (TGFBR2)” refers to a protein that in humans is encoded by the gene TGFBR2, or its orthologs. Swiss-Prot accession number P37173 provides exemplary human TGFBR2 amino acid sequences. Exemplary immature human TGFBR2 amino acid sequences are provided in SEQ ID NOs: 98 and 99. Exemplary mature human TGFBR2 amino acid sequences are provided in SEQ ID NOs: 123 and 124. As used herein, a “TGFBR2 polypeptide” refers to a TGFBR2 or its fragment, or variant thereof.

[0196] As used herein, the term “transforming growth factor beta receptor type 3 (TGFBR3)” refers to a protein that in humans is encoded by the gene TGFBR3, or its orthologs. Swiss-Prot accession number Q03167 provides exemplary human TGFBR3 amino acid sequences. Exemplary immature human TGFBR3 amino acid sequences are provided in SEQ ID NOs: 106 and 107. Exemplary mature human TGFBR3 aminoacid sequences are provided in SEQ ID NOs: 125 and 126. As used herein, a “TGFBR3 polypeptide” refers to a TGFBR3 or its fragment, or variant thereof.

[0197] As used herein, “cancer” as used herein can encompass all types of oncogenic processes and / or cancerous growths. In some embodiments, cancer includes primary tumors as well as metastatic tissues or malignantly transformed cells, tissues, or organs. In some embodiments, cancer encompasses all histopathologies and stages, e.g., stages of invasiveness / severity, of a cancer. In some embodiments, cancer includes relapsed and / or resistant cancer. The terms “cancer” and “tumor” can be used interchangeably. For example, both terms encompass solid and liquid tumors. As used herein, the term “cancer” or “tumor” includes premalignant, as well as malignant cancers and tumors.

[0198] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In the case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and are not intended to be limiting.

[0199] Various aspects of the invention are described in further detail below. Additional definitions are set out throughout the specification. Other features and advantages of the invention will be apparent from the following detailed description and claims.ANTI-G6B ANTIBODY MOLECULE AND ANTI-CD34 ANTIBODY MOLECULEAnti-G6B Antibody

[0200] In some embodiments, the anti-G6B antibody or binding fragment thereof comprises a heavy chain variable domain (VH) comprising a heavy chain complementarity determining region 3 (HC CDR3) of any one of the sequences selected from the group consisting of SEQ ID NOs: 204, 208, 211, 215, 219, 223, and 227. In some embodiments, the anti-G6B antibody or binding fragment thereof comprises a VH comprising a HC CDR3 comprising an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to any one of the sequences selected from the group consisting of SEQ ID NOs: 204, 208, 211, 215, 219, 223, and 227.

[0201] In some embodiments, the anti-G6B antibody or binding fragment thereof comprises a VH comprising a HC CDR3 of any one of the HC CDR3 sequences listed in Table 3. In some embodiments, the anti-G6B antibody or binding fragment thereof comprises a VH comprising a HC CDR3 comprising an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to any one of the HC CDR3 sequences listed in Table 3.

[0202] In some embodiments, the VH of the anti-G6B antibody or binding fragment thereof comprises a heavy chain complementarity determining region 1 (HC CDR1) of any one of the sequences selected fromthe group consisting of SEQ ID NOs: 202, 206, 213, 217, 221, and 225. In some embodiments, the VH of the anti-G6B antibody or binding fragment thereof comprises a HC CDR1 comprising an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to any one of the sequences selected from the group consisting of SEQ ID NOs: 202, 206, 213, 217, 221, and 225.

[0203] In some embodiments, the VH of the anti-G6B antibody or binding fragment thereof comprises a HC CDR1 of any one of the HC CDR1 sequences listed in Table 3. In some embodiments, the VH of the anti-G6B antibody or binding fragment thereof comprises a HC CDR1 comprising an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to any one of the HC CDR1 sequences listed in Table 3.

[0204] In some embodiments, the VH of the anti-G6B antibody or binding fragment thereof comprises a heavy chain complementarity determining region 2 (HC CDR2) of any one of the sequences selected from the group consisting of SEQ ID NOs: 203, 207, 210, 214, 218, 222, and 226. In some embodiments, the VH of the anti-G6B antibody or binding fragment thereof comprises a HC CDR2 comprising an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to any one of the sequences selected from the group consisting of SEQ ID NOs: 203, 207, 210, 214, 218, 222, and 226.

[0205] In some embodiments, the VH of the anti-G6B antibody or binding fragment thereof comprises a HC CDR2 of any one of the HC CDR2 sequences listed in Table 3. In some embodiments, the VH of the anti-G6B antibody or binding fragment thereof comprises a HC CDR2 comprising an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to any one of the HC CDR2 sequences listed in Table 3.

[0206] In some embodiments, the anti-G6B antibody or binding fragment thereof comprises a light chain variable domain (VL) comprising a light chain complementarity determining region 3 (LC CDR3) of any one of the sequences selected from the group consisting of SEQ ID NOs: 231, 235, 239, 243, 247, 250, 254, 258, 262, 266, 270, 274, and 278. In some embodiments, the anti-G6B antibody or binding fragment thereof comprises a VL comprising a LC CDR3 comprising an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to any one of the sequences selected from the group consisting of SEQ ID NOs: 231, 235, 239, 243, 247, 250, 254, 258, 262, 266, 270, 274, and 278.

[0207] In some embodiments, the anti-G6B antibody or binding fragment thereof comprises a VL comprising a LC CDR3 of any one of the LC CDR3 sequences listed in Table 3. In some embodiments, the anti-G6B antibody or binding fragment thereof comprises a VL comprising a LC CDR3 comprising an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to any one of the LC CDR3 sequences listed in Table 3.

[0208] In some embodiments, the VL of the anti-G6B antibody or binding fragment thereof comprises alight chain complementarity determining region 1 (LC CDR1) of any one of the sequences selected from the group consisting of SEQ ID NOs: 229, 233, 237, 241, 245, 252, 256, 260, 264, 268, 272, and 276. In some embodiments, the VL of the anti-G6B antibody or binding fragment thereof comprises a LC CDR1 comprising an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to any one of the sequences selected from the group consisting of SEQ ID NOs: 229, 233, 237, 241, 245, 252, 256, 260, 264, 268, 272, and 276.

[0209] In some embodiments, the VL of the anti-G6B antibody or binding fragment thereof comprises a LC CDR1 of any one of the LC CDR1 sequences listed in Table 3. In some embodiments, the VL of the anti-G6B antibody or binding fragment thereof comprises a LC CDR1 comprising an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to any one of the LC CDR1 sequences listed in Table 3.

[0210] In some embodiments, the VL of the anti-G6B antibody or binding fragment thereof comprises a light chain complementarity determining region 2 (LC CDR2) of any one of the sequences selected from the group consisting of SEQ ID NOs: 230, 234, 238, 242, 246, 249, 253, 257, 261, 265, 269, 273, and 277. In some embodiments, the VL of the anti-G6B antibody or binding fragment thereof comprises a LC CDR2 comprising an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to any one of the sequences selected from the group consisting of SEQ ID NOs: 230, 234, 238, 242, 246, 249, 253, 257, 261, 265, 269, 273, and 277.

[0211] In some embodiments, the VL of the anti-G6B antibody or binding fragment thereof comprises a LC CDR2 of any one of the LC CDR2 sequences listed in Table 3. In some embodiments, the VL of the anti-G6B antibody or binding fragment thereof comprises a LC CDR2 comprising an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to any one of the LC CDR2 sequences listed in Table 3.

[0212] In some embodiments, the anti-G6B antibody or binding fragment thereof comprises: (i) the VH comprising the HC CDR1 of any one of the sequences selected from the group consisting of SEQ ID NOs: 202, 206, 213, 217, 221, and 225, the HC CDR2 of any one of the sequences selected from the group consisting of SEQ ID NOs: 203, 207, 210, 214, 218, 222, and 226, and the HC CDR3 of any one of the sequences selected from the group consisting of SEQ ID NOs: 204, 208, 211, 215, 219, 223, and 227; (ii) the VL comprising the LC CDR1 of any one of the sequences selected from the group consisting of SEQ ID NOs: 229, 233, 237, 241, 245, 252, 256, 260, 264, 268, 272, and 276, the LC CDR2 of any one of the sequences selected from the group consisting of SEQ ID NOs: 230, 234, 238, 242, 246, 249, 253, 257, 261, 265, 269, 273, and 277, and the LC CDR3 of any one of the sequences selected from the group consisting of SEQ ID NOs: 231, 235, 239, 243, 247, 250, 254, 258, 262, 266, 270, 274, and 278; or (iii) any combination thereof. In some embodiments, the anti-G6B antibody or binding fragment thereof comprises: (i) the VH comprising the HC CDR1 comprising an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to anyone of the sequences selected from the group consisting of SEQ ID NOs: 202, 206, 213, 217, 221, and 225, the HC CDR2 comprising an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to any one of the sequences selected from the group consisting of SEQ ID NOs: 203, 207, 210, 214, 218, 222, and 226, and the HC CDR3 comprising an ammo acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to any one of the sequences selected from the group consisting of SEQ ID NOs: 204, 208, 211, 215, 219, 223, and 227; (ii) the VL comprising the LC CDR1 comprising an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to any one of the sequences selected from the group consisting of SEQ ID NOs: 229, 233, 237, 241, 245, 252, 256, 260, 264, 268, 272, and 276, the LC CDR2 comprising an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to any one of the sequences selected from the group consisting of SEQ ID NOs: 230, 234, 238, 242, 246, 249, 253, 257, 261, 265, 269, 273, and 277, and the LC CDR3 comprising an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to any one of the sequences selected from the group consisting of SEQ ID NOs: 231, 235, 239, 243, 247, 250, 254, 258, 262, 266, 270, 274, and 278; or (iii) any combination thereof.

[0213] In some embodiments, the anti-G6B antibody or binding fragment thereof comprises: (i) the VH comprising the HC CDR1 of any one of the HC CDR1 sequences listed in Table 3, the HC CDR2 of any one of the HC CDR2 sequences listed in Table 3, and the HC CDR3 of any one of the HC CDR3 sequences listed in Table 3; (ii) the VL comprising the LC CDR1 of any one of the LC CDR1 sequences listed in Table 3, the LC CDR2 of any one of the LC CDR1 sequences listed in Table 3, and the LC CDR3 of any one of the LC CDR1 sequences listed in Table 3; or (iii) any combination thereof. In some embodiments, the anti- G6B antibody or binding fragment thereof comprises: (i) the VH comprising the HC CDR1 comprising an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to any one of the HC CDR1 sequences listed in Table 3, the HC CDR2 comprising an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to any one of the HC CDR2 sequences listed in Table 3, and the HC CDR3 comprising an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%,99.8%, 99.9% sequence identity to any one of the HC CDR3 sequences listed in Table 3; (ii) the VL comprising the LC CDR1 comprising an ammo acid sequence with at least 50%, 55%, 60%, 65%, 70%,75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to any one of the LC CDR1 sequences listed in Table 3, the LC CDR2 comprising an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%,99.8%, 99.9% sequence identity to any one of the LC CDR2 sequences listed in Table 3, and the LC CDR3comprising an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to any one of the LC CDR3 sequences listed in Table 3; or (iii) any combination thereof.

[0214] In some embodiments, the anti-G6B antibody or binding fragment thereof comprises: (i) the VH comprising a HC CDR1, a HC CDR2 and a HC CDR3 of SEQ ID NOs: 202, 203, and 204, respectively; SEQ ID NOs: 206, 207, and 208, respectively; SEQ ID NOs: 206, 210, and 211, respectively; SEQ ID NOs: 213, 214, and 215, respectively; SEQ ID NOs: 217, 218, and 219, respectively; SEQ ID NOs: 221, 222, and 223, respectively; or SEQ ID NOs: 225, 226, and 227, respectively; (ii) the VL comprising a LC CDR1, a LC CDR2 and a LC CDR3 of SEQ ID NOs: 229, 230, and 231, respectively; SEQ ID NOs: 233, 234, and 235, respectively; SEQ ID NOs: 237, 238, and 239, respectively; SEQ ID NOs: 241, 242, and 243, respectively; SEQ ID NOs: 245, 246, and 247, respectively; SEQ ID NOs: 245, 249, and 250, respectively; SEQ ID NOs: 252, 253, and 254, respectively; SEQ ID NOs: 256, 257, and 258, respectively; SEQ ID NOs: 260, 261, and 262, respectively; SEQ ID NOs: 264, 265, and 266, respectively; SEQ ID NOs: 268, 269, and 270, respectively; SEQ ID NOs: 272, 273, and 274, respectively; or SEQ ID NOs: 276, 277, and 278, respectively; or (iii) any combination thereof.

[0215] In some embodiments, the anti-G6B antibody or binding fragment thereof comprises: (i) a VH comprising an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 201, 205, 209, 212, 216, 220, and 224; (ii) a VL comprising an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 228, 232, 236, 240, 244, 248, 251, 255, 259, 263, 267, 271, and 275; or (iii) any combination thereof. In some embodiments, the anti-G6B antibody or binding fragment thereof comprises: (i) a VH comprising a sequence selected from the group consisting of SEQ ID NOs: 201, 205, 209, 212, 216, 220, and 224; (ii) a VL comprising a sequence selected from the group consisting of SEQ ID NOs: 228, 232, 236, 240, 244, 248, 251, 255, 259, 263, 267, 271, and 275; or (iii) any combination thereof. In some embodiments, the anti-G6B antibody or binding fragment thereof comprises: (i) a VH of any one of the sequences of SEQ ID NOs: 201, 205, 209, 212, 216, 220, and 224; (ii) a VL of any one of the sequences of SEQ ID NOs: 228, 232, 236, 240, 244, 248, 251, 255, 259, 263, 267, 271, and 275; or (iii) any combination thereof.

[0216] In some embodiments, the anti-G6B antibody or binding fragment thereof comprises: (i) a VH comprising an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to a VH sequence listed in Table 3; (ii) a VL comprising an ammo acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to a VL sequence listed in Table 3; or (iii) any combination thereof. In some embodiments, the anti-G6B antibody or binding fragment thereof comprises: (i) a VH comprising a VH sequence listed in Table 3; (ii) a VL comprising a VL sequence listed in Table 3; or (iii) any combination thereof. In some embodiments, the anti-G6Bantibody or binding fragment thereof comprises: (i) a VH of any one of a VH sequence listed in Table 3; (ii) a VL of any one of a VL sequence listed in Table 3; or (iii) any combination thereof.

[0217] In some embodiments, the anti-G6B antibody or binding fragment thereof comprises: a VH of SEQ ID NO: 201 and a VL of SEQ ID NO: 228; a VH of SEQ ID NO: 201 and aVL of SEQ ID NO: 232; a VH of SEQ ID NO : 201 and a VL of SEQ ID NO : 236; a VH of SEQ ID NO : 201 and a VL of SEQ ID NO : 240; a VH of SEQ ID NO: 201 and a VL of SEQ ID NO: 244; a VH of SEQ ID NO: 201 and a VL of SEQ ID NO: 248; a VH of SEQ ID NO: 201 and a VL of SEQ ID NO: 251; a VH of SEQ ID NO: 201 and a VL of SEQ ID NO : 255 ; a VH of SEQ ID NO : 201 and a VL of SEQ ID NO : 259; a VH of SEQ ID NO : 201 and a VL of SEQ ID NO: 263; a VH of SEQ ID NO: 201 and aVL of SEQ ID NO: 267; a VH of SEQ ID NO : 201 and a VL of SEQ ID NO : 271 ; a VH of SEQ ID NO : 201 and a VL of SEQ ID NO : 275 ; a VH of SEQ ID NO: 205 and a VL of SEQ ID NO: 228; a VH of SEQ ID NO: 205 and a VL of SEQ ID NO: 232; a VH of SEQ ID NO: 205 and a VL of SEQ ID NO: 236; a VH of SEQ ID NO: 205 and a VL of SEQ ID NO: 240; a VH of SEQ ID NO: 205 and a VL of SEQ ID NO: 244; a VH of SEQ ID NO: 205 and a VL of SEQ ID NO: 248; a VH of SEQ ID NO: 205 and a VL of SEQ ID NO: 251; a VH of SEQ ID NO: 205 and a VL of SEQ ID NO: 255; a VH of SEQ ID NO: 205 and a VL of SEQ ID NO: 259; a VH of SEQ ID NO: 205 and a VL of SEQ ID NO: 263; a VH of SEQ ID NO: 205 and a VL of SEQ ID NO: 267; a VH of SEQ ID NO : 205 and a VL of SEQ ID NO : 271 ; a VH of SEQ ID NO : 205 and a VL of SEQ ID NO : 275 ; a VH of SEQ ID NO: 209 and a VL of SEQ ID NO: 228; a VH of SEQ ID NO: 209 and a VL of SEQ ID NO: 232; a VH of SEQ ID NO: 209 and a VL of SEQ ID NO: 236; a VH of SEQ ID NO: 209 and a VL of SEQ ID NO: 240; a VH of SEQ ID NO: 209 and a VL of SEQ ID NO: 244; a VH of SEQ ID NO: 209 and a VL of SEQ ID NO: 248; a VH of SEQ ID NO: 209 and a VL of SEQ ID NO: 251; a VH of SEQ ID NO: 209 and a VL of SEQ ID NO: 255; a VH of SEQ ID NO: 209 and a VL of SEQ ID NO: 259; a VH of SEQ ID NO: 209 and a VL of SEQ ID NO: 263; a VH of SEQ ID NO: 209 and a VL of SEQ ID NO: 267; a VH of SEQ ID NO : 209 and a VL of SEQ ID NO : 271 ; a VH of SEQ ID NO : 209 and a VL of SEQ ID NO : 275 ; a VH of SEQ ID NO: 212 and a VL of SEQ ID NO: 228; a VH of SEQ ID NO: 212 and a VL of SEQ ID NO: 232; a VH of SEQ ID NO: 212 and a VL of SEQ ID NO: 236; a VH of SEQ ID NO: 212 and a VL of SEQ ID NO: 240; a VH of SEQ ID NO: 212 and a VL of SEQ ID NO: 244; a VH of SEQ ID NO: 212 and a VL of SEQ ID NO: 248; a VH of SEQ ID NO: 212 and a VL of SEQ ID NO: 251; a VH of SEQ ID NO: 212 and a VL of SEQ ID NO: 255; a VH of SEQ ID NO: 212 and a VL of SEQ ID NO: 259; a VH of SEQ ID NO: 212 and a VL of SEQ ID NO: 263; a VH of SEQ ID NO: 212 and a VL of SEQ ID NO: 267; a VH of SEQ ID NO : 212 and a VL of SEQ ID NO : 271 ; a VH of SEQ ID NO : 212 and a VL of SEQ ID NO : 275 ; a VH of SEQ ID NO: 216 and a VL of SEQ ID NO: 228; a VH of SEQ ID NO: 216 and a VL of SEQ ID NO: 232; a VH of SEQ ID NO : 216 and a VL of SEQ ID NO : 236; a VH of SEQ ID NO : 216 and a VL of SEQ ID NO : 240; a VH of SEQ ID NO: 216 and a VL of SEQ ID NO: 244; a VH of SEQ ID NO: 216 and a VL of SEQ ID NO: 248; a VH of SEQ ID NO: 216 and a VL of SEQ ID NO: 251; a VH of SEQ ID NO: 216 and a VL of SEQ ID NO: 255; a VH of SEQ ID NO: 216 and a VL of SEQ ID NO: 259; a VH of SEQ ID NO: 216 and a VL of SEQ ID NO: 263; a VH of SEQ ID NO: 216 and a VL of SEQ ID NO: 267; a VH of SEQ IDNO : 216 and a VL of SEQ ID NO : 271 ; a VH of SEQ ID NO : 216 and a VL of SEQ ID NO : 275 ; a VH of SEQ ID NO: 220 and a VL of SEQ ID NO: 228; a VH of SEQ ID NO: 220 and a VL of SEQ ID NO: 232; a VH of SEQ ID NO: 220 and a VL of SEQ ID NO: 236; a VH of SEQ ID NO: 220 and a VL of SEQ ID NO: 240; a VH of SEQ ID NO: 220 and a VL of SEQ ID NO: 244; a VH of SEQ ID NO: 220 and a VL of SEQ ID NO: 248; a VH of SEQ ID NO: 220 and a VL of SEQ ID NO: 251; a VH of SEQ ID NO: 220 and a VL of SEQ ID NO: 255; a VH of SEQ ID NO: 220 and a VL of SEQ ID NO: 259; a VH of SEQ ID NO: 220 and a VL of SEQ ID NO: 263; a VH of SEQ ID NO: 220 and a VL of SEQ ID NO: 267; a VH of SEQ ID NO : 220 and a VL of SEQ ID NO : 271 ; a VH of SEQ ID NO : 220 and a VL of SEQ ID NO : 275 ; a VH of SEQ ID NO: 224 and a VL of SEQ ID NO: 228; a VH of SEQ ID NO: 224 and a VL of SEQ ID NO: 232; a VH of SEQ ID NO: 224 and a VL of SEQ ID NO: 236; a VH of SEQ ID NO: 224 and a VL of SEQ ID NO: 240; a VH of SEQ ID NO: 224 and a VL of SEQ ID NO: 244; a VH of SEQ ID NO: 224 and a VL of SEQ ID NO: 248; a VH of SEQ ID NO: 224 and a VL of SEQ ID NO: 251; a VH of SEQ ID NO: 224 and a VL of SEQ ID NO: 255; a VH of SEQ ID NO: 224 and a VL of SEQ ID NO: 259; a VH of SEQ ID NO: 224 and a VL of SEQ ID NO: 263; a VH of SEQ ID NO: 224 and a VL of SEQ ID NO: 267; a VH of SEQ ID NO: 224 and a VL of SEQ ID NO: 271; or a VH of SEQ ID NO: 224 and a VL of SEQ ID NO: 275.

[0218] In some embodiments, the anti-G6B antibody or binding fragment thereof is a full-length antibody, a Fab, a F(ab')2, an Fv, a single chain Fv, a single domain antibody, a half arm antibody, a diabody (dAb), a bivalent antibody, a monovalent antibody, a bispecific antibody or fragment thereof, or a camelid antibody. In some embodiments, the anti-G6B antibody or binding fragment thereof is the scFv, wherein the scFv comprises a VH and a VL operatively linked by a linker.

[0219] In some embodiments, the linker is selected from the group consisting of a cleavable linker, a non- cleavable linker, a peptide linker, a flexible linker, a rigid linker, a helical linker, and a non-helical linker. In some embodiments, the linker is the peptide linker, and wherein the linker comprises any one of the sequences selected from the group consisting of SEQ ID NOs: 69-72 and 295. In some embodiments, the linker is the peptide linker comprising any one of the sequences listed in Table 6.

[0220] In some embodiments, the anti-G6B antibody or binding fragment thereof is a murine, human, or humanized antibody or binding fragment thereof.

[0221] In some embodiments, the VH of anti-G6B antibody or binding fragment thereof is linked to a constant heavy chain 1 domain. In some embodiments, the CHI linked to the VH of anti-G6B antibody or binding fragment thereof is a CHI of IgGl, IgG2, IgG3, IgGAl, IgGA2, IgG4, IgJ, IgM, IgD, or IgE. In some embodiments, the CHI linked to the VH of anti-G6B antibody or binding fragment thereof comprise any one of the CHI sequences selected from the group consisting of SEQ ID NOs: 299, 300, and 302-309. In some embodiments, the CHI linked to the VH of anti-G6B antibody or binding fragment thereof comprises an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to any one of the CHI sequences selected from the group consisting of SEQ ID NOs: 299, 300, and 302-309.

[0022] In some embodiments, the VL of the anti-G6B antibody or binding fragment thereof is linked to aconstant light chain domain (CL), In some embodiments, the CL linked to the VL of the anti-G6B antibody or binding fragment thereof is a CL of a lambda light chain or a CL of a kappa light chain. In some embodiments, the CL linked to the VL of the anti-G6B antibody or binding fragment thereof comprises any one of the sequences selected from the group consisting of SEQ ID NOs: 297 and 298. In some embodiments, the CL linked to the VL of the anti-G6B antibody or binding fragment thereof comprises an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to any one of the sequences selected from the group consisting of SEQ ID NOs: 297 and 298.

[0223] In some embodiments, the CHI linked to the VH of anti-G6B antibody or binding fragment thereof comprise any one of the CHI sequences listed in Table 5. In some embodiments, the CHI linked to the VH of anti-G6B antibody or binding fragment thereof comprises an ammo acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to any one of the CHI sequences listed in Table 5.

[0224] In some embodiments, the CL linked to the VL of the anti-G6B antibody or binding fragment thereof comprises any one of the CL sequences listed in Table 5. In some embodiments, the CL linked to the VL of the anti-G6B antibody or binding fragment thereof comprises an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to any one of the CL sequences listed in Table 5.

[0225] In some embodiments, the composition further comprises any one selected from the group consisting of an antigen binding moiety, an immune cell engager, a cytokine molecule, a modulator of a cytokine molecule, a stromal modifying moiety, and any combination thereof, and wherein the immune cell engager is selected from the group consisting of a T cell engager, an NK cell engager, a B cell engager, a dendritic cell engager, and a macrophage cell engager. In some embodiments, the anti-G6B antibody or binding fragment thereof is linked to the antigen binding moiety, the immune cell engager, the cytokine molecule, the modulator of a cytokine molecule, the stromal modifying moiety, or any combination thereof. In some embodiments, the anti-G6B antibody or binding fragment thereof is linked to the antigen binding moiety, the immune cell engager, the cytokine molecule, the modulator of a cytokine molecule, the stromal modifying moiety, or any combination thereof by a linker.

[0226] In some embodiments, the antigen binding moiety is a tumor targeting moiety. In some embodiments, the antigen binding moiety is an anti-CD34 antibody or binding fragment thereof.

[0227] In some embodiments, the modulator of a cytokine molecule is a TGF-beta inhibitor. In some embodiments, the TGF-beta inhibitor comprises an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to any one sequence selected from the group consisting of the extracellular domain sequences of SEQ ID NOs: 93-99, 106, 107, 117-119, 120-126, and 200. In some embodiments, the TGF-beta inhibitor comprises an amino acid sequence of any one sequence selected from the group consisting of the extracellular domain sequences of SEQ ID NOs: 93-99, 106, 107, 117-119, 120-126, and 200.

[0228] In some embodiments, the TGF-beta inhibitor comprises an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 100-105 and 108. In some embodiments, the TGF-beta inhibitor comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 100-105 and 108. In some embodiments, the sequence of the TGF-beta inhibitor is an amino acid sequence selected from the group consisting of SEQ ID NOs: 100-105 and 108.

[0229] In some embodiments, the anti-G6B antibody or binding fragment thereof is linked to an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 192-199. In some embodiments, the anti-G6B antibody or binding fragment thereof is linked to an amino acid sequence selected from the group consisting of SEQ ID NOs: 192-199.

[0230] In some embodiments, the anti-G6B antibody or binding fragment thereof targets the TGF-beta inhibitor to the bone marrow stromal niche when administered to a subject. In some embodiments, the anti- G6B antibody or binding fragment thereof targets the TGF-beta inhibitor to a malignant haematopoietic stem cell or a progenitor cell in the bone marrow stromal niche when administered to a subject.

[0231] In another aspect, provided herein a method of targeting a TGF-beta inhibitor to a bone marrow stromal niche in a subject, the method comprises administering the composition comprising the anti-G6B antibody or binding fragment thereof as provided herein or the anti-G6B antibody or binding fragment thereof as provided herein to a subject in need thereof, wherein the TCF-beta inhibitor is targeted to the bone marrow stromal niche in the subject. In some embodiments, the TGF-beta inhibitor is targeted to a malignant haematopoietic stem cell or a progenitor cell in the bone marrow stromal niche in the subject.Anti-CD34 Antibody

[0232] In some embodiments, the anti-CD34 antibody or binding fragment thereof comprises a heavy chain variable domain (VH) comprising a heavy chain complementarity determining region 3 (HC CDR3) of SEQ ID NO: 282. In some embodiments, the anti-CD34 antibody or binding fragment thereof comprises a VH comprising a HC CDR3 comprising an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to the sequences of SEQ ID NO: 282.

[0233] In some embodiments, the anti-CD34 antibody or binding fragment thereof comprises a VH comprising a HC CDR3 of any one of the HC CDR3 sequences listed in Table 4. In some embodiments, the anti-CD34 antibody or binding fragment thereof comprises a VH comprising a HC CDR3 comprising an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to any one of the HC CDR3 sequences listed in Table 4.

[0234] In some embodiments, the VH of the anti-CD34 antibody or binding fragment thereof comprises a heavy chain complementarity determining region 1 (HC CDR1) of SEQ ID NO: 281. In some embodiments,the VH of the anti-CD34 antibody or binding fragment thereof comprises a HC CDR1 comprising an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to the sequences of SEQ ID NO: 281.

[0235] In some embodiments, the VH of the anti-CD34 antibody or binding fragment thereof comprises a HC CDR1 of any one of the HC CDR1 sequences listed in Table 4. In some embodiments, the VH of the anti-CD34 antibody or binding fragment thereof comprises a HC CDR1 comprising an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to any one of the HC CDR1 sequences listed in Table 4.

[0236] In some embodiments, the VH of the anti-CD34 antibody or binding fragment thereof comprises a heavy chain complementarity determining region 2 (HC CDR2) of SEQ ID NO: 280. In some embodiments, the VH of the anti-CD34 antibody or binding fragment thereof comprises a HC CDR2 comprising an ammo acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to the sequences of SEQ ID NO: 280.

[0237] In some embodiments, the VH of the anti-CD34 antibody or binding fragment thereof comprises a HC CDR2 of any one of the HC CDR2 sequences listed in Table 4. In some embodiments, the VH of the anti-CD34 antibody or binding fragment thereof comprises a HC CDR2 comprising an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to any one of the HC CDR2 sequences listed in Table 4.

[0238] In some embodiments, the anti-CD34 antibody or binding fragment thereof comprises a light chain variable domain (VL) comprising a light chain complementarity determining region 3 (LC CDR3) of SEQ ID NO: 291. In some embodiments, the anti-CD34 antibody or binding fragment thereof comprises a VL comprising a LC CDR3 comprising an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to the sequences of SEQ ID NO: 291.

[0239] In some embodiments, the anti-CD34 antibody or binding fragment thereof comprises a VL comprising a LC CDR3 of any one of the LC CDR3 sequences listed in Table 4. In some embodiments, the anti-CD34 antibody or binding fragment thereof comprises a VL comprising a LC CDR3 comprising an ammo acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to any one of the LC CDR3 sequences listed in Table 4.

[0240] In some embodiments, the VL of the anti-CD34 antibody or binding fragment thereof comprises a light chain complementarity determining region 1 (LC CDR1) of SEQ ID NO: 290. In some embodiments, the VL of the anti-CD34 antibody or binding fragment thereof comprises a LC CDR1 comprising an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to the sequences of SEQ ID NO: 290.

[0241] In some embodiments, the VL of the anti-CD34 antibody or binding fragment thereof comprises a LC CDR1 of any one of the LC CDR1 sequences listed in Table 4. In some embodiments, the VL of theanti-CD34 or binding fragment thereof comprises a LC CDR1 comprising an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to any one of the LC CDR1 sequences listed in Table 4.

[0242] In some embodiments, the VL of the anti-CD34 antibody or binding fragment thereof comprises a light chain complementarity determining region 2 (LC CDR2) of SEQ ID NO: 289. In some embodiments, the VL of the anti-CD34 antibody or binding fragment thereof comprises a LC CDR2 comprising an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to the sequences of SEQ ID NO: 289.

[0243] In some embodiments, the VL of the anti-CD34 antibody or binding fragment thereof comprises a LC CDR2 of any one of the LC CDR2 sequences listed in Table 4. In some embodiments, the VL of the anti-CD34 or binding fragment thereof comprises a LC CDR2 comprising an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to any one of the LC CDR2 sequences listed in Table 4.

[0244] In some embodiments, the anti-CD34 antibody or binding fragment thereof comprises: (i) the VH comprising the HC CDR1 of SEQ ID NO: 280, the HC CDR2 of SEQ ID NO: 281, and the HC CDR3 of SEQ ID NO: 282; (ii) the VL comprising the LC CDR1 of SEQ ID NO: 289, the LC CDR2 of SEQ ID NO: 290, and the LC CDR3 of SEQ ID NO: 291; or (iii) any combination thereof.

[0245] In some embodiments, the anti-CD34 antibody or binding fragment thereof comprises: (i) the VH comprising the HC CDR1 comprising an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to the sequence of SEQ ID NO: 280, the HC CDR2 comprising an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to the sequence of SEQ ID NO: 281, and the HC CDR3 comprising an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to the sequence of SEQ ID NO: 282; (ii) the VL comprising the LC CDR1 comprising an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to the sequence of SEQ ID NO: 289, the LC CDR2 comprising an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to the sequence of SEQ ID NO: 290, and the LC CDR3 comprising an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to the sequence of SEQ ID NO: 291; or (iii) any combination thereof.

[0246] In some embodiments, the anti-CD34 antibody or binding fragment thereof comprises: (i) the VH comprising the HC CDR1 of any one of the HC CDR1 sequences listed in Table 4, the HC CDR2 of any one of the HC CDR2 sequences listed in Table 4, and the HC CDR3 of any one of the HC CDR3 sequences listed in Table 4; (ii) the VL comprising the LC CDR1 of any one of the LC CDR1 sequences listed in Table 4, the LC CDR2 of any one of the LC CDR2 sequences listed in Table 4, and the LC CDR3 of any one ofthe LC CDR3 sequences listed in Table 4; or (iii) any combination thereof.

[0247] In some embodiments, the anti-CD34 antibody or binding fragment thereof comprises: (i) the VH comprising the HC CDR1 comprising an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to any one of the HC CDR1 sequences listed in Table 4, the HC CDR2 comprising an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to any one of the HC CDR2 sequences listed in Table 4, and the HC CDR3 comprising an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to any one of the HC CDR3 sequences listed in Table 4; (ii) the VL comprising the LC CDR1 comprising an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to any one of the LC CDR1 sequences listed in Table 4, the LC CDR2 comprising an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to any one of the LC CDR2 sequences listed in Table 4, and the LC CDR3 comprising an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to any one of the LC CDR3 sequences listed in Table 4; or (iii) any combination thereof.

[0248] In some embodiments, the anti-CD34 antibody or binding fragment thereof comprises: (i) a VH comprising an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 279, 283, 284, 285, 286, and 287; (ii) a VL comprising an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 288, 292, 293, and 294; or (iii) any combination thereof. In some embodiments, the anti-CD34 antibody or binding fragment thereof comprises: (i) a VH comprising a sequence selected from the group consisting of SEQ ID NOs: 279, 283, 284, 285, 286, and 287; (ii) a VL comprising a sequence selected from the group consisting of SEQ ID NOs: 292, 293, and 294; or (iii) any combination thereof. In some embodiments, the anti-CD34 antibody or binding fragment thereof comprises: (i) a VH of any one of the sequence of SEQ ID NOs: 279, 283, 284, 285, 286, and 287; (ii) a VL of any one of the sequence of SEQ ID NOs: 292, 293, and 294; or (iii) any combination thereof.

[0249] In some embodiments, the anti-CD34 antibody or binding fragment thereof comprises: (i) a VH comprising an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to a VH sequence listed in Table 4; (ii) a VL comprising an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to a VL sequence listed in Table 4; or (iii) any combination thereof. In some embodiments, the anti-CD34 antibody or binding fragment thereof comprises: (i) a VH comprising a VH sequence listed in Table 4; (ii) a VL comprising aVL sequence listed in Table 4; or (iii) any combination thereof. In some embodiments, the anti-CD34 antibody or binding fragment thereof comprises: (i) a VH of any one of a VH sequence listed in Table 4; (ii) a VL of any one of a VL sequence listed in Table 4; or (iii) any combination thereof.

[0250] In some embodiments, the anti-CD34 antibody or binding fragment thereof comprises: a VH of SEQ ID NO: 279 and a VL of SEQ ID NO: 292; a VH of SEQ ID NO: 279 and a VL of SEQ ID NO: 293; a VH of SEQ ID NO: 279 and a VL of SEQ ID NO: 294; a VH of SEQ ID NO: 283 and a VL of SEQ ID NO: 292; a VH of SEQ ID NO: 283 and a VL of SEQ ID NO: 293; a VH of SEQ ID NO: 283 and a VL of SEQ ID NO: 294; a VH of SEQ ID NO: 284 and a VL of SEQ ID NO: 292; a VH of SEQ ID NO: 284 and a VL of SEQ ID NO: 293; a VH of SEQ ID NO: 284 and a VL of SEQ ID NO: 294; a VH of SEQ ID NO: 285 and a VL of SEQ ID NO: 292; a VH of SEQ ID NO: 285 and a VL of SEQ ID NO: 293; a VH of SEQ ID NO: 285 and a VL of SEQ ID NO: 294; a VH of SEQ ID NO: 286 and a VL of SEQ ID NO: 292; a VH of SEQ ID NO: 286 and a VL of SEQ ID NO: 293; a VH of SEQ ID NO: 286 and a VL of SEQ ID NO: 294; a VH of SEQ ID NO: 287 and a VL of SEQ ID NO: 292; a VH of SEQ ID NO: 287 and a VL of SEQ ID NO: 293; or a VH of SEQ ID NO: 287 and a VL of SEQ ID NO: 294.

[0251] In some embodiments, the anti-CD34 antibody or binding fragment thereof is a full-length antibody, a Fab, a F(ab')2, an Fv, a single chain Fv, a single domain antibody, a half arm antibody, a diabody (dAb), a bivalent antibody, a monovalent antibody, a bispecific antibody or fragment thereof, or a camelid antibody.

[0252] In some embodiments, the anti-CD34 antibody or binding fragment thereof is the scFv, wherein the scFv comprises a VH and a VL operatively linked by a linker. In some embodiments, the linker is selected from the group consisting of a cleavable linker, a non-cleavable linker, a peptide linker, a flexible linker, a rigid linker, a helical linker, and a non-helical linker. In some embodiments, the linker is the peptide linker, and wherein the linker comprises any one of the sequences selected from SEQ ID NOs: 69-72 and 295. In some embodiments, the linker is the peptide linker comprising any one of the sequences listed in Table 6.

[0253] In some embodiments, the anti-CD34 antibody or binding fragment thereof is a murine, human, or humanized antibody or binding fragment thereof.

[0254] In some embodiments, the VH of anti-CD34 antibody or binding fragment thereof is linked to a constant heavy chain 1 domain. In some embodiments, the CHI linked to the VH of anti-CD34 antibody or binding fragment thereof is a CHI of IgGl, IgG2, IgG3, IgGAl, IgGA2, IgG4, IgJ, IgM, IgD, or IgE. In some embodiments, the CHI linked to the VH of anti-CD34 antibody or binding fragment thereof comprise any one of the CHI sequences selected from SEQ ID NOs: 299, 300, and 302-309. In some embodiments, the CHI linked to the VH of anti-CD34 antibody or binding fragment thereof comprises an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to any one of the CHI sequences selected from the group consisting of SEQ ID NOs: 299, 300, and 302-309.

[0255] In some embodiments, the VL of the anti-CD34 antibody or binding fragment thereof is linked toa constant light chain domain (CL). In some embodiments, the CL linked to the VL of the anti-CD34 antibody or binding fragment thereof is a CL of a lambda light chain or a CL of a kappa light chain. In some embodiments, the CL linked to the VL of the anti-CD34 antibody or binding fragment thereof comprises any one of the sequences selected from the group consisting of SEQ ID NOs: 297 and 298. In some embodiments, the CL linked to the VL of the anti-CD34 antibody or binding fragment thereof comprises an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to any one of the sequences selected from the group consisting of SEQ ID NOs: 297 and 298.

[0256] In some embodiments, the CHI linked to the VH of anti-CD34 antibody or binding fragment thereof comprise any one of the CHI sequences listed in Table 5. In some embodiments, the CHI linked to the VH of anti-CD34 antibody or binding fragment thereof comprises an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to any one of the CHI sequences listed in Table 5.

[0257] In some embodiments, the CL linked to the VL of the anti-CD34 antibody or binding fragment thereof comprises any one of the CL sequences listed in Table 5. In some embodiments, the CL linked to the VL of the anti-CD34 antibody or binding fragment thereof comprises an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to any one of the CL sequences listed in Table 5.

[0258] Additional Exemplary anti-CD34 antibody sequences

[0259] In one aspect, provided herein is a multispecific or multifunctional molecule comprising a tumor targeting moiety that comprises a CD34-targeting moiety. In another aspect, provided herein is an anti-CD34 antibody molecule (e.g., a monoclonal anti-CD34 antibody molecule).

[0260] In some embodiments, the CD34-targeting moiety or anti-CD34 antibody molecule comprises an antibody, or an antigen-binding fragment thereof, disclosed in Table 3 or Table 4. In some embodiments, the CD34-targeting moiety or anti-CD34 antibody molecule comprises a CDR, a framework region, or a variable region sequence disclosed in Table 4 (or a sequence having at least about 75%, 80%, 85%, 90%, 95%, or 99% sequence identity thereto).

[0261] In some embodiments, the CD34-targeting moiety or anti-CD34 antibody molecule comprises a VH comprising a heavy chain complementarity determining region 1 (VHCDR1) amino acid sequence of SEQ ID NO: 87 (or a sequence with no more than 1, 2, 3, or 4 mutations, e.g., substitutions, additions, or deletions), a VHCDR2 amino acid sequence of SEQ ID NO: 88 (or a sequence with no more than 1, 2, 3, or 4 mutations, e.g., substitutions, additions, or deletions), and / or a VHCDR3 amino acid sequence of SEQ ID NO: 89 (or a sequence with no more than 1, 2, 3, or 4 mutations, e.g., substitutions, additions, or deletions). In some embodiments, the CD34-targeting moiety or anti-CD34 antibody molecule comprises a VH comprising a VHCDR1 amino acid sequence of SEQ ID NO: 87, a VHCDR2 amino acid sequence of SEQ ID NO: 88, and / or a VHCDR3 amino acid sequence of SEQ ID NO: 89. In some embodiments, the CD34-targeting moiety or anti-CD34 antibody molecule comprises a VL comprising a light chain complementarity determining region 1 (VLCDR1) amino acid sequence of SEQ ID NO: 90 (or a sequence with no more than1, 2, 3, or 4 mutations, e.g., substitutions, additions, or deletions), a VLCDR2 amino acid sequence of SEQ ID NO: 91 (or a sequence with no more than 1, 2, 3, or 4 mutations, e.g., substitutions, additions, or deletions), and / or a VLCDR3 amino acid sequence of SEQ ID NO: 92 (or a sequence with no more than 1,2, 3, or 4 mutations, e.g., substitutions, additions, or deletions). In some embodiments, the CD34-targeting moiety or anti-CD34 antibody molecule comprises a VL comprising a VLCDR1 amino acid sequence of SEQ ID NO: 90, a VLCDR2 amino acid sequence of SEQ ID NO: 91, and a VLCDR3 amino acid sequence of SEQ ID NO: 92.

[0262] In some embodiments, the CD34-targeting moiety or anti-CD34 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 79, 80, 81, or 82, or an amino acid sequence having at least about 80%, 85%, 90%, 95%, or 99% sequence identity thereto. In some embodiments, the CD34-targeting moiety or anti-CD34 antibody molecule comprises a VL comprising the amino acid sequence of SEQ ID NO: 83, 84, 85, or 86, or an amino acid sequence having at least about 80%, 85%, 90%, 95%, or 99% sequence identity thereto. In some embodiments, the CD34-targeting moiety or anti-CD34 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 79 (or an amino acid sequence having at least about 80%, 85%, 90%, 95%, or 99% sequence identity thereto) and a VL comprising the amino acid sequence of SEQ ID NO: 83 (or an amino acid sequence having at least about 80%, 85%, 90%, 95%, or 99% sequence identity thereto). In some embodiments, the CD34-targeting moiety or anti-CD34 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 79 and a VL comprising the amino acid sequence of SEQ ID NO: 83. In some embodiments, the CD34- targeting moiety or anti-CD34 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 80 (or an amino acid sequence having at least about 80%, 85%, 90%, 95%, or 99% sequence identity thereto) and a VL comprising the amino acid sequence of SEQ ID NO: 83 (or an amino acid sequence having at least about 80%, 85%, 90%, 95%, or 99% sequence identity thereto). In some embodiments, the CD34-targeting moiety or anti-CD34 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 80 and a VL comprising the amino acid sequence of SEQ ID NO: 83. In some embodiments, the CD34-targeting moiety or anti-CD34 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 81 (or an amino acid sequence having at least about 80%, 85%, 90%, 95%, or 99% sequence identity thereto) and a VL comprising the amino acid sequence of SEQ ID NO: 83 (or an amino acid sequence having at least about 80%, 85%, 90%, 95%, or 99% sequence identity thereto). In some embodiments, the CD34-targeting moiety or anti-CD34 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 81 and a VL comprising the amino acid sequence of SEQ ID NO: 83. In some embodiments, the CD34-targeting moiety or anti-CD34 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 82 (or an amino acid sequence having at least about 80%, 85%, 90%, 95%, or 99% sequence identity thereto) and a VL comprising the amino acid sequence of SEQ ID NO: 83 (or an amino acid sequence having at least about80%, 85%, 90%, 95%, or 99% sequence identity thereto). In some embodiments, the CD34-targeting moiety or anti-CD34 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 82 and a VL comprising the amino acid sequence of SEQ ID NO: 83. In some embodiments, the CD34- targeting moiety or anti-CD34 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 79 (or an amino acid sequence having at least about 80%, 85%, 90%, 95%, or 99% sequence identity thereto) and a VL comprising the amino acid sequence of SEQ ID NO: 84 (or an amino acid sequence having at least about 80%, 85%, 90%, 95%, or 99% sequence identity thereto). In some embodiments, the CD34-targeting moiety or anti-CD34 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 79 and a VL comprising the amino acid sequence of SEQ ID NO: 84. In some embodiments, the CD34-targeting moiety or anti-CD34 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 80 (or an amino acid sequence having at least about 80%, 85%, 90%, 95%, or 99% sequence identity thereto) and a VL comprising the amino acid sequence of SEQ ID NO: 84 (or an amino acid sequence having at least about 80%, 85%, 90%, 95%, or 99% sequence identity thereto). In some embodiments, the CD34-targeting moiety or anti-CD34 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 80 and a VL comprising the amino acid sequence of SEQ ID NO: 84. In some embodiments, the CD34-targeting moiety or anti-CD34 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 81 (or an amino acid sequence having at least about 80%, 85%, 90%, 95%, or 99% sequence identity thereto) and a VL comprising the amino acid sequence of SEQ ID NO: 84 (or an amino acid sequence having at least about 80%, 85%, 90%, 95%, or 99% sequence identity thereto). In some embodiments, the CD34-targeting moiety or anti-CD34 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 81 and a VL comprising the amino acid sequence of SEQ ID NO: 84. In some embodiments, the CD34- targeting moiety or anti-CD34 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 82 (or an amino acid sequence having at least about 80%, 85%, 90%, 95%, or 99% sequence identity thereto) and a VL comprising the amino acid sequence of SEQ ID NO: 84 (or an amino acid sequence having at least about 80%, 85%, 90%, 95%, or 99% sequence identity thereto). In some embodiments, the CD34-targeting moiety or anti-CD34 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 82 and a VL comprising the amino acid sequence of SEQ ID NO: 84. In some embodiments, the CD34-targeting moiety or anti-CD34 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 79 (or an amino acid sequence having at least about 80%, 85%, 90%, 95%, or 99% sequence identity thereto) and a VL comprising the amino acid sequence of SEQ ID NO: 85 (or an amino acid sequence having at least about 80%, 85%, 90%, 95%, or 99% sequence identity thereto). In some embodiments, the CD34-targeting moiety or anti-CD34 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 79 and a VL comprising the amino acid sequence of SEQ ID NO: 85. In some embodiments, the CD34-targeting moiety or anti-CD34 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 80 (or an amino acid sequence having at least about 80%, 85%, 90%, 95%, or 99% sequence identity thereto) and a VLcomprising the amino acid sequence of SEQ ID NO: 85 (or an amino acid sequence having at least about 80%, 85%, 90%, 95%, or 99% sequence identity thereto). In some embodiments, the CD34-targeting moiety or anti-CD34 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 80 and a VL comprising the amino acid sequence of SEQ ID NO: 85. In some embodiments, the CD34- targeting moiety or anti-CD34 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 81 (or an amino acid sequence having at least about 80%, 85%, 90%, 95%, or 99% sequence identity thereto) and a VL comprising the amino acid sequence of SEQ ID NO: 85 (or an amino acid sequence having at least about 80%, 85%, 90%, 95%, or 99% sequence identity thereto). In some embodiments, the CD34-targeting moiety or anti-CD34 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 81 and a VL comprising the amino acid sequence of SEQ ID NO: 85. In some embodiments, the CD34-targeting moiety or anti-CD34 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 82 (or an amino acid sequence having at least about 80%, 85%, 90%, 95%, or 99% sequence identity thereto) and a VL comprising the amino acid sequence of SEQ ID NO: 85 (or an amino acid sequence having at least about 80%, 85%, 90%, 95%, or 99% sequence identity thereto). In some embodiments, the CD34-targeting moiety or anti-CD34 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 82 and a VL comprising the amino acid sequence of SEQ ID NO: 85. In some embodiments, the CD34-targeting moiety or anti-CD34 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 79 (or an amino acid sequence having at least about 80%, 85%, 90%, 95%, or 99% sequence identity thereto) and a VL comprising the amino acid sequence of SEQ ID NO: 86 (or an amino acid sequence having at least about 80%, 85%, 90%, 95%, or 99% sequence identity thereto). In some embodiments, the CD34-targeting moiety or anti-CD34 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 79 and a VL comprising the amino acid sequence of SEQ ID NO: 86. In some embodiments, the CD34- targeting moiety or anti-CD34 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 80 (or an amino acid sequence having at least about 80%, 85%, 90%, 95%, or 99% sequence identity thereto) and a VL comprising the amino acid sequence of SEQ ID NO: 86 (or an amino acid sequence having at least about 80%, 85%, 90%, 95%, or 99% sequence identity thereto). In some embodiments, the CD34-targeting moiety or anti-CD34 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 80 and a VL comprising the amino acid sequence of SEQ ID NO: 86. In some embodiments, the CD34-targeting moiety or anti-CD34 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 81 (or an amino acid sequence having at least about 80%, 85%, 90%, 95%, or 99% sequence identity thereto) and a VL comprising the amino acid sequence of SEQ ID NO: 86 (or an amino acid sequence having at least about 80%, 85%, 90%, 95%, or 99% sequence identity thereto). In some embodiments, the CD34-targeting moiety or anti-CD34 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 81 and a VL comprising the amino acid sequence of SEQ ID NO: 86. In some embodiments, the CD34-targeting moiety or anti-CD34 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 82 (or an amino acidsequence having at least about 80%, 85%, 90%, 95%, or 99% sequence identity thereto) and a VL comprising the amino acid sequence of SEQ ID NO: 86 (or an amino acid sequence having at least about 80%, 85%, 90%, 95%, or 99% sequence identity thereto). In some embodiments, the CD34-targeting moiety or anti-CD34 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 82 and a VL comprising the amino acid sequence of SEQ ID NO: 86. In some embodiments, the CD34- targeting moiety or anti-CD34 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 79 and a VL comprising the amino acid sequence of SEQ ID NO: 84.

[0263] In some embodiments, the composition further comprises any one selected from the group consisting of an antigen binding moiety, an immune cell engager, a cytokine molecule, a modulator of a cytokine molecule, a stromal modifying moiety, and any combination thereof, and wherein the immune cell engager is selected from the group consisting of a T cell engager, an NK cell engager, a B cell engager, a dendritic cell engager, and a macrophage cell engager.

[0264] In some embodiments, the anti-CD34 antibody or binding fragment thereof is linked to the antigen binding moiety, the immune cell engager, the cytokine molecule, the modulator of a cytokine molecule, the stromal modifying moiety, or any combination thereof. In some embodiments, the anti-CD34 antibody or binding fragment thereof is linked to the antigen binding moiety, the immune cell engager, the cytokine molecule, the modulator of a cytokine molecule, the stromal modifying moiety, or any combination thereof by a linker.

[0265] In some embodiments, the antigen binding moiety is a tumor targeting moiety.

[0266] In some embodiments, the antigen binding moiety is an anti-G6B antibody or binding fragment thereof.Antibody Molecules

[0267] In some embodiments, an antibody molecule is a monospecific antibody molecule and binds a single epitope. E.g., a monospecific antibody molecule having a plurality of immunoglobulin variable domain sequences, each of which binds the same epitope.

[0268] In some embodiments, an antibody molecule comprises a diabody, and a single-chain molecule, as well as an antigen-binding fragment thereof of an antibody (e.g., Fab, F(ab’)2, and Fv). For example, an antibody molecule can include a heavy (H) chain variable domain sequence (abbreviated herein as VH), and a light (L) chain variable domain sequence (abbreviated herein as VL). In some embodiments, an antibody molecule comprises or consists of a heavy chain and a light chain (referred to herein as a half antibody. In another example, an antibody molecule includes two heavy (H) chain variable domain sequences and two light (L) chain variable domain sequence, thereby forming two antigen binding sites, such as Fab, Fab’, F(ab’)2, Fc, Fd, Fd’, Fv, single chain antibodies (scFv for example), single variable domain antibodies, diabodies (Dab) (bivalent and bispecific), and chimeric (e.g., humanized) antibodies, which may be produced by the modification of whole antibodies orthose synthesized de novo using recombinant DNA technologies. These functional antibody fragments retain the ability to selectively bind with their respectiveantigen or receptor. Antibodies and antibody fragments can be from any class of antibodies including, but not limited to, IgG, IgA, IgM, IgD, and IgE, and from any subclass (e.g., IgGl, IgG2, IgG3, and IgG4) of antibodies. The a preparation of antibody molecules can be monoclonal or polyclonal. An antibody molecule can also be a human, humanized, CDR-grafted, or in vitro generated antibody. The antibody can have a heavy chain constant region selected from, e.g., IgGl, IgG2, IgG3, and IgG4. The antibody can also have a light chain selected from, e.g., kappa and lambda. The term “immunoglobulin” (Ig) is used interchangeably with the term “antibody” herein.

[0269] Examples of antigen-binding fragments thereof of an antibody molecule include: (i) a Fab fragment, a monovalent fragment consisting of the VL, VH, CL and CHI domains; (ii) a F(ab')2 fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; (iii) a Fd fragment consisting of the VH and CHI domains; (iv) a Fv fragment consisting of the VL and VH domains of a single arm of an antibody, (v) a diabody (dAb) fragment, which consists of a VH domain; (vi) a camelid or camelized variable domain; (vii) a single chain Fv (scFv), see e.g., Bird et al. (1988) Science 242:423- 426; and Huston et al. (1988) Proc. Natl. Acad. Sci. USA 85:5879-5883); (viii) a single domain antibody. These antibody fragments are obtained using conventional techniques known to those with skill in the art, and the fragments are screened for utility in the same manner as are intact antibodies.

[0270] Antibody molecules include intact molecules as well as functional fragments thereof. Constant regions of the antibody molecules can be altered, e.g., mutated, to modify the properties of the antibody (e.g., to increase or decrease one or more of: Fc receptor binding, antibody glycosylation, the number of cysteine residues, effector cell function, or complement function).

[0271] Antibody molecules can also be single domain antibodies. Single domain antibodies can include antibodies whose complementary determining regions are part of a single domain polypeptide. Examples include, but are not limited to, heavy chain antibodies, antibodies naturally devoid of light chains, single domain antibodies derived from conventional 4-chain antibodies, engineered antibodies and single domain scaffolds other than those derived from antibodies. Single domain antibodies may be any of the art, or any future single domain antibodies. Single domain antibodies may be derived from any species including, but not limited to mouse, human, camel, llama, fish, shark, goat, rabbit, and bovine. According to another aspect of the invention, a single domain antibody is a naturally occurring single domain antibody known as heavy chain antibody devoid of light chains. Such single domain antibodies are disclosed in WO 9404678, for example. For clarity reasons, this variable domain derived from a heavy chain antibody naturally devoid of light chain is known herein as a VHH or nanobody to distinguish it from the conventional VH of four chain immunoglobulins. Such a VHH molecule can be derived from antibodies raised in Camelidae species, for example in camel, llama, dromedary, alpaca and guanaco. Other species besides Camelidae may produce heavy chain antibodies naturally devoid of light chain; such VHHs are within the scope of the invention.

[0272] The VH and VL regions can be subdivided into regions of hypervariability, termed "complementarity determining regions" (CDR), interspersed with regions that are more conserved, termed "framework regions" (FR or FW).

[0273] The extent of the framework region and CDRs has been precisely defined by a number of methods (see, Kabat, E. A., et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No. 91-3242; Chothia, C. et al. (1987) J. Mol. Biol. 196:901-917; and the AbM definition used by Oxford Molecular's AbM antibody modeling software. See, generally, e.g., Protein Sequence and Structure Analysis of Antibody Variable Domains. In: Antibody Engineering Lab Manual (Ed.: Duebel, S. and Kontermann, R., Springer-Verlag, Heidelberg).

[0274] The terms “complementarity determining region,” and “CDR,” as used herein refer to the sequences of amino acids within antibody variable regions which confer antigen specificity and binding affinity. In general, there are three CDRs in each heavy chain variable region (HCDR1, HCDR2, HCDR3) and three CDRs in each light chain variable region (LCDR1, LCDR2, LCDR3).

[0275] The precise amino acid sequence boundaries of a given CDR can be determined using any of a number of known schemes, including those described by Kabat et al. (1991), “Sequences of Proteins of Immunological Interest,” 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD (“Kabat” numbering scheme), Al-Lazikani et al., (1997) JMB 273,927-948 (“Chothia” numbering scheme). As used herein, the CDRs defined according the “Chothia” number scheme are also sometimes referred to as “hypervariable loops.”

[0276] For example, under Kabat, the CDR amino acid residues in the heavy chain variable domain (VH) are numbered 31-35 (HCDR1), 50-65 (HCDR2), and 95-102 (HCDR3); and the CDR amino acid residues in the light chain variable domain (VL) are numbered 24-34 (LCDR1), 50-56 (LCDR2), and 89-97 (LCDR3). Under Chothia, the CDR amino acids in the VH are numbered 26-32 (HCDR1), 52-56 (HCDR2), and 95- 102 (HCDR3); and the amino acid residues in VL are numbered 26-32 (LCDR1), 50-52 (LCDR2), and 91- 96 (LCDR3).

[0277] Each VH and VL typically includes three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4.

[0278] The antibody molecule can be a polyclonal or a monoclonal antibody.

[0279] The terms "monoclonal antibody" or "monoclonal antibody composition" as used herein refer to a preparation of antibody molecules of single molecular composition. A monoclonal antibody composition displays a single binding specificity and affinity for a particular epitope. A monoclonal antibody can be made by hybridoma technology or by methods that do not use hybridoma technology (e.g., recombinant methods).

[0280] The antibody can be recombinantly produced, e.g., produced by phage display or by combinatorial methods.

[0281] Phage display and combinatorial methods for generating antibodies are known in the art (as described in, e.g., Ladner et al. U.S. Patent No. 5,223,409; Kang et al. International Publication No. WO 92 / 18619; Dower et al. International Publication No. WO 91 / 17271; Winter et al. International Publication WO 92 / 20791; Markland et al. International Publication No. WO 92 / 15679; Breitling et al. International Publication WO 93 / 01288; McCafferty et al. International Publication No. WO 92 / 01047; Garrard et al.International Publication No. WO 92 / 09690; Ladner et al. International Publication No. WO 90 / 02809; Fuchs et al. (1991) Bio / Technology 9: 1370-1372; Hay et al. (1992) Hum Antibod Hybridomas 3:81-85; Huse et al. (1989) Science 246: 1275-1281; Griffths et al. (1993) EMBO J 12:725-734; Hawkins et al. (1992) J Mol Biol 226:889-896; Clackson et al. (1991) Nature 352:624-628; Gram et al. (1992) PNAS 89:3576- 3580; Garrad et al. (1991) Bio / Technology 9: 1373-1377; Hoogenboom et al. (1991) Nuc Acid Res 19:4133- 4137; and Barbas et al. (1991) PNAS 88:7978-7982, the contents of all of which are incorporated by reference herein).

[0282] In some embodiments, the antibody is a fully human antibody (e.g., an antibody made in a mouse which has been genetically engineered to produce an antibody from a human immunoglobulin sequence), or a non-human antibody, e.g., a rodent (mouse or rat), goat, primate (e.g., monkey), camel antibody.Preferably, the non-human antibody is a rodent (mouse or rat antibody). Methods of producing rodent antibodies are known in the art.

[0283] Human monoclonal antibodies can be generated using transgenic mice carrying the human immunoglobulin genes rather than the mouse system. Splenocytes from these transgenic mice immunized with the antigen of interest are used to produce hybridomas that secrete human mAbs with specific affinities for epitopes from a human protein (see, e.g., Wood et al. International Application WO 91 / 00906, Kucherlapati et al. PCT publication WO 91 / 10741; Lonberg et al. International Application WO 92 / 03918; Kay et al. International Application 92 / 03917; Lonberg, N. et al. 1994 Nature 368:856-859; Green, L.L. et al. 1994 Nature Genet. 7: 13-21; Morrison, S.L. et al. 1994 Proc. Natl. Acad. Sci. USA 81:6851-6855;Bruggeman et al. 1993 Year Immunol 7:33-40; Tuaillon et al. 1993 PNAS 90:3720-3724; Bruggeman et al. 1991 Eur J Immunol 21: 1323-1326).

[0284] An antibody molecule can be one in which the variable region, or a portion thereof, e.g., the CDRs, are generated in a non-human organism, e.g., a rat or mouse. Chimeric, CDR-grafted, and humanized antibodies are within the invention. Antibody molecules generated in a non-human organism, e.g., a rat or mouse, and then modified, e.g., in the variable framework or constant region, to decrease antigenicity in a human are within the invention.

[0285] An “effectively human” protein is a protein that does substantially not evoke a neutralizing antibody response, e.g., the human anti-murine antibody (HAMA) response. HAMA can be problematic in a number of circumstances, e.g., if the antibody molecule is administered repeatedly, e.g., in treatment of a chronic or recurrent disease condition. A HAMA response can make repeated antibody administration potentially ineffective because of an increased antibody clearance from the serum (see, e.g., Saleh et al., Cancer Immunol. Immunother., 32: 180-190 (1990)) and also because of potential allergic reactions (see, e.g., LoBuglio et al., Hybridoma, 5:5117-5123 (1986)).

[0286] Chimeric antibodies can be produced by recombinant DNA techniques known in the art (see Robinson et al., International Patent Publication PCT / US86 / 02269; Akira, et al., European Patent Application 184,187; Taniguchi, M., European Patent Application 171,496; Morrison et al., European Patent Application 173,494; Neuberger et al., International Application WO 86 / 01533; Cabilly et al. U.S. PatentNo. 4,816,567; Cabilly et al., European Patent Application 125,023; Better et al. (1988 Science 240: 1041- 1043); Liu et al. (1987) PNAS 84:3439-3443; Liu et al., 1987, J. Immunol. 139:3521-3526; Sun et al. (1987) PNAS 84:214-218; Nishimura et al., 1987, Cane. Res. 47:999-1005; Wood et al. (1985) Nature 314:446- 449; and Shaw et al., 1988, J. Natl Cancer Inst. 80: 1553-1559).

[0287] A humanized or CDR-grafted antibody will have at least one or two but generally all three recipient CDRs (of heavy and or light immuoglobulin chains) replaced with a donor CDR. The antibody may be replaced with at least a portion of a non-human CDR or only some of the CDRs may be replaced with non-human CDRs. It is only necessary to replace the number of CDRs required for binding to the antigen. Preferably, the donor will be a rodent antibody, e.g., a rat or mouse antibody, and the recipient will be a human framework or a human consensus framework. Typically, the immunoglobulin providing the CDRs is called the "donor" and the immunoglobulin providing the framework is called the "acceptor." In some embodiments, the donor immunoglobulin is a non-human (e.g., rodent). The acceptor framework is a naturally-occurring (e.g., a human) framework or a consensus framework, or a sequence about 85% or higher, preferably 90%, 95%, 99% or higher identical thereto.

[0288] As used herein, the term "consensus sequence" refers to the sequence formed from the most frequently occurring amino acids (or nucleotides) in a family of related sequences (See e.g., Winnaker, Prom Genes to Clones (Verlagsgesellschaft, Weinheim, Germany 1987). In a family of proteins, each position in the consensus sequence is occupied by the amino acid occurring most frequently at that position in the family. If two amino acids occur equally frequently, either can be included in the consensus sequence. A "consensus framework" refers to the framework region in the consensus immunoglobulin sequence.

[0289] An antibody molecule can be humanized by methods known in the art (see e.g., Morrison, S. L., 1985, Science 229: 1202-1207, by Oi et al., 1986, BioTechniques 4:214, and by Queen et al. US 5,585,089, US 5,693,761 and US 5,693,762, the contents of all of which are hereby incorporated by reference).

[0290] Humanized or CDR-grafted antibody molecules can be produced by CDR-grafting or CDR substitution, wherein one, two, or all CDRs of an immunoglobulin chain can be replaced. See e.g., U.S. Patent 5,225,539; Jones et al. 1986 Nature 321:552-525; Verhoeyan et al. 1988 Science 239: 1534; Beidler et al. 1988 J. Immunol. 141:4053-4060; Winter US 5,225,539, the contents of all of which are hereby expressly incorporated by reference. Winter describes a CDR-grafting method which may be used to prepare the humanized antibodies of the present invention (UK Patent Application GB 2188638A, filed on March 26, 1987; Winter US 5,225,539), the contents of which is expressly incorporated by reference.

[0291] Also within the scope of the invention are humanized antibody molecules in which specific amino acids have been substituted, deleted or added. Criteria for selecting amino acids from the donor are described in US 5,585,089, e.g., columns 12-16 of US 5,585,089, e.g., columns 12-16 of US 5,585,089, the contents of which are hereby incorporated by reference. Other techniques for humanizing antibodies are described in Padlan et al. EP 519596 Al, published on December 23, 1992.

[0292] The antibody molecule can be a single chain antibody. A single-chain antibody (scFv) may be engineered (see, for example, Colcher, D. et al. (1999) Ann N Y Acad Sci 880:263-80; and Reiter, Y. (1996)Clin Cancer Res 2:245-52). The single chain antibody can be dimerized or multimerized to generate multivalent antibodies having specificities for different epitopes of the same target protein.

[0293] In yet other embodiments, the antibody molecule has a heavy chain constant region selected from, e.g., the heavy chain constant regions of IgGl, IgG2, IgG3, IgG4, IgM, IgAl, IgA2, IgD, and IgE; particularly, selected from, e.g., the (e.g., human) heavy chain constant regions of IgGl, IgG2, IgG3, and IgG4. In another embodiment, the antibody molecule has a light chain constant region selected from, e.g., the (e.g., human) light chain constant regions of kappa and lambda. The constant region can be altered, e.g., mutated, to modify the properties of the antibody (e.g., to increase or decrease one or more of: Fc receptor binding, antibody glycosylation, the number of cysteine residues, effector cell function, and / or complement function). In some embodiments the antibody has: effector function; and can fix complement. In other embodiments the antibody does not; recruit effector cells; or fix complement. In another embodiment, the antibody has reduced or no ability to bind an Fc receptor. For example, it is a isotype or subtype, fragment or other mutant, which does not support binding to an Fc receptor, e.g., it has a mutagenized or deleted Fc receptor binding region.

[0294] Methods for altering an antibody constant region are known in the art. Antibodies with altered function, e.g. altered affinity for an effector ligand, such as FcR on a cell, or the Cl component of complement can be produced by replacing at least one amino acid residue in the constant portion of the antibody with a different residue (see e.g., EP 388,151 Al, U.S. Pat. No. 5,624,821 and U.S. Pat. No. 5,648,260, the contents of all of which are hereby incorporated by reference). Similar type of alterations could be described which if applied to the murine, or other species immunoglobulin would reduce or eliminate these functions.

[0295] An antibody molecule can be derivatized or linked to another functional molecule (e.g., another peptide or protein). As used herein, a "derivatized" antibody molecule is one that has been modified. Methods of derivatization include but are not limited to the addition of a fluorescent moiety, a radionucleotide, a toxin, an enzyme or an affinity ligand such as biotin. Accordingly, the antibody molecules of the invention are intended to include derivatized and otherwise modified forms of the antibodies described herein, including immunoadhesion molecules. For example, an antibody molecule can be functionally linked (by chemical coupling, genetic fusion, noncovalent association or otherwise) to one or more other molecular entities, such as another antibody (e.g., a bispecific antibody or a diabody), a detectable agent, a cytotoxic agent, a pharmaceutical agent, and / or a protein or peptide that can mediate association of the antibody or antibody portion with another molecule (such as a streptavidin core region or a polyhistidine tag).

[0296] One type of derivatized antibody molecule is produced by crosslinking two or more antibodies (of the same type or of different types, e.g., to create bispecific antibodies). Suitable crosslinkers include those that are heterobifunctional, having two distinctly reactive groups separated by an appropriate spacer (e.g., m- maleimidobenzoyl-N-hydroxysuccinimide ester) or homobifunctional (e.g., disuccinimidyl suberate). Such linkers are available from Pierce Chemical Company, Rockford, Ill.

[0297] In some embodiments, the antibody molecule binds to a cancer antigen, e.g., a tumor antigen or a stromal antigen. In some embodiments, the cancer antigen is, e.g., a mammalian, e.g., a human, cancer antigen. In other embodiments, the antibody molecule binds to an immune cell antigen, e.g., a mammalian, e.g., a human, immune cell antigen. For example, the antibody molecule binds specifically to an epitope, e.g., linear or conformational epitope, on the cancer antigen or the immune cell antigen.

[0298] CDR-grafted scaffolds

[0299] In some embodiments, the antibody molecule is a CDR-grafted scaffold domain. In some embodiments, the scaffold domain is based on a fibronectin domain, e.g., fibronectin type III domain. The overall fold of the fibronectin type III (Fn3) domain is closely related to that of the smallest functional antibody fragment, the variable domain of the antibody heavy chain. There are three loops at the end of Fn3; the positions of BC, DE and FG loops approximately correspond to those of CDR1, 2 and 3 of the VH domain of an antibody. Fn3 does not have disulfide bonds; and therefore Fn3 is stable under reducing conditions, unlike antibodies and their fragments (see, e.g., WO 98 / 56915; WO 01 / 64942; WO 00 / 34784). An Fn3 domain can be modified (e.g., using CDRs or hypervariable loops described herein) or varied, e.g., to select domains that bind to an antigen / marker / cell described herein.

[0300] In some embodiments, a scaffold domain, e.g., a folded domain, is based on an antibody, e.g., a “minibody” scaffold created by deleting three beta strands from a heavy chain variable domain of a monoclonal antibody (see, e.g., Tramontane et al., 1994, J Mol. Recognit. 7:9; and Martin et al., 1994, EMBO J. 13:5303-5309). The “minibody” can be used to present two hypervariable loops. In some embodiments, the scaffold domain is a V-like domain (see, e.g., Coia et al. WO 99 / 45110) or a domain derived from tendami statin, which is a 74 residue, six-strand beta sheet sandwich held together by two disulfide bonds (see, e.g., McConnell and Hoess, 1995, J Mol. Biol. 250:460). For example, the loops of tendamistatin can be modified (e.g., using CDRs or hypervariable loops) or varied, e.g., to select domains that bind to a marker / antigen / cell described herein. Another exemplary scaffold domain is a beta-sandwich structure derived from the extracellular domain of CTLA-4 (see, e.g., WO 00 / 60070).

[0301] Other exemplary scaffold domains include but are not limited to T-cell receptors; MHC proteins; extracellular domains (e.g., fibronectin Type III repeats, EGF repeats); protease inhibitors (e.g., Kunitz domains, ecotin, BPTI, and so forth); TPR repeats; trifoil structures; zinc finger domains; DNA-binding proteins; particularly monomeric DNA binding proteins; RNA binding proteins; enzymes, e.g., proteases (particularly inactivated proteases), RNase; chaperones, e.g., thioredoxin, and heat shock proteins; and intracellular signaling domains (such as SH2 and SH3 domains). See, e.g., US 20040009530 and US 7,501,121, incorporated herein by reference.

[0302] In some embodiments, a scaffold domain is evaluated and chosen, e.g., by one or more of the following criteria: (1) amino acid sequence, (2) sequences of several homologous domains, (3) 3- dimensional structure, and / or (4) stability data over a range of pH, temperature, salinity, organic solvent, oxidant concentration. In some embodiments, the scaffold domain is a small, stable protein domain, e.g., aprotein of less than 100, 70, 50, 40 or 30 amino acids. The domain may include one or more disulfide bonds or may chelate a metal, e.g., zinc.

[0303] Antibody-Based Fusions

[0304] A variety of formats can be generated which contain additional binding entities attached to the N or C terminus of antibodies. These fusions with single chain or disulfide stabilized Fvs or Fabs result in the generation of tetravalent molecules with bivalent binding specificity for each antigen. Combinations of scFvs and scFabs with IgGs enable the production of molecules which can recognize three or more different antigens.

[0305] Antibody-Fab Fusion

[0306] Antibody -Fab fusions are bispecific antibodies comprising a traditional antibody to a first target and a Fab to a second target fused to the C terminus of the antibody heavy chain. Commonly the antibody and the Fab will have a common light chain. Antibody fusions can be produced by (1 ) engineering the DNA sequence of the target fusion, and (2) transfecting the target DNA into a suitable host cell to express the fusion protein. It seems like the antibody-scFv fusion may be linked by a (Gly)-Ser linker between the C- terminus of the CH3 domain and the N-terminus of the scFv, as described by Coloma, J. et al. (1997) Nature Biotech 15: 159.

[0307] Antibody-scFv Fusion

[0308] Antibody-scFv Fusions are bispecific antibodies comprising a traditional antibody and a scFv of unique specificity fused to the C terminus of the antibody heavy chain. The scFv can be fused to the C terminus through the Heavy Chain of the scFv either directly or through a linker peptide. Antibody fusions can be produced by (1) engineering the DNA sequence of the target fusion, and (2) transfecting the target DNA into a suitable host cell to express the fusion protein. It seems like the antibody-scFv fusion may be linked by a (Gly)-Ser linker between the C-terminus of the CH3 domain and the N-terminus of the scFv, as described by Coloma, J. et al. (1997) Nature Biotech 15: 159.

[0309] Variable Domain Immunoglobulin DVD

[0310] A related format is the dual variable domain immunoglobulin (DVD), which are composed of VH and VL domains of a second specificity place upon the N termini of the V domains by shorter linker sequences.

[0311] Fc-containing entities (mini-antibodies)

[0312] Fc-containing entities, also known as mini-antibodies, can be generated by fusing scFv to the C- termini of constant heavy region domain 3 (CH3-scFv) and / or to the hinge region (scFv-hinge-Fc) of an antibody with a different specificity. Trivalent entities can also be made which have disulfide stabilizedvariable domains (without peptide linker) fused to the C-terminus of CH3 domains of IgGs.MULTIFUNCTIONAL MOLECULES

[0313] In some embodiments, the multifunctional molecule comprises an anti-G6B antibody or binding fragment thereof linked to an antigen binding moiety, wherein the anti-G6B antibody or binding fragment thereof comprises a heavy chain variable domain (VH) comprising a heavy chain complementarity' determining region 3 (HC CDR3) of any one of the sequences selected from the group consisting of SEQ ID NOs: 204, 208, 211, 215, 219, 223, and 227. In some embodiments, the anti-G6B antibody or binding fragment thereof comprises a VH comprising a HC CDR3 comprising an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to any one of the sequences selected from the group consisting of SEQ ID NOs: 204, 208, 211, 215, 219, 223, and 227. In some embodiments, the anti-G6B antibody or binding fragment thereof comprises a VH comprising a HC CDR3 of any one of the HC CDR3 sequences listed in Table 3. In some embodiments, the anti-G6B antibody or binding fragment thereof comprises a VH comprising a HC CDR3 comprising an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to any one of the HC CDR3 sequences listed in Table 3.

[0314] In some embodiments, the antigen binding moiety is an anti-CD34 antibody or binding fragment thereof. In some embodiments, the anti-CD34 antibody or binding fragment thereof comprises a heavy chain variable domain (VH) comprising a heavy chain complementarity determining region 3 (HC CDR3) of SEQ ID NO: 282. In some embodiments, the anti-CD34 antibody or binding fragment thereof comprises a VH comprising a HC CDR3 comprising an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to the sequences of SEQ ID NO: 282. In some embodiments, the anti-CD34 antibody or binding fragment thereof comprises a VH comprising a HC CDR3 of any one of the HC CDR3 sequences listed in Table 4. In some embodiments, the anti-CD34 antibody or binding fragment thereof comprises a VH comprising a HC CDR3 comprising an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to any one of the HC CDR3 sequences listed in Table 4.

[0315] In some embodiments, the multifunctional molecule comprises an anti-CD34 antibody or binding fragment thereof linked to an antigen binding moiety, wherein the anti-CD34 antibody or binding fragment thereof comprises a heavy chain variable domain (VH) comprising a heavy chain complementarity determining region 3 (HC CDR3) of SEQ ID NO: 282. In some embodiments, the anti-CD34 antibody or binding fragment thereof comprises a VH comprising a HC CDR3 comprising an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to the sequences of SEQ ID NO: 282. In some embodiments, the anti-CD34 antibody or binding fragment thereof comprises a VH comprising a HC CDR3 of any one of the HC CDR3sequences listed in Table 4. In some embodiments, the anti-CD34 antibody or binding fragment thereof comprises a VH comprising a HC CDR3 comprising an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to any one of the HC CDR3 sequences listed in Table 4.

[0316] In some embodiments, the antigen binding moiety is an anti-G6B antibody or binding fragment thereof. In some embodiments, the anti-G6B antibody or binding fragment thereof comprises a heavy chain variable domain (VH) comprising a heavy chain complementarity determining region 3 (HC CDR3) of any one of the sequences selected from the group consisting of SEQ ID NOs: 204, 208, 211, 215, 219, 223, and 227.

[0317] In some embodiments, the VH of the anti-G6B antibody or binding fragment thereof further comprises a heavy chain complementarity determining region 1 (HC CDR1) of any one of the sequences selected from the group consisting of SEQ ID NOs: 202, 206, 213, 217, 221, and 225. In some embodiments, the VH of the anti-G6B antibody or binding fragment thereof comprises a HC CDR1 comprising an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to any one of the sequences selected from the group consisting of SEQ ID NOs: 202, 206, 213, 217, 221, and 225. In some embodiments, the VH of the anti-G6B antibody or binding fragment thereof comprises a HC CDR1 of any one of the HC CDR1 sequences listed in Table 3. In some embodiments, the VH of the anti-G6B antibody or binding fragment thereof comprises a HC CDR1 comprising an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to any one of the HC CDR1 sequences listed in Table 3.

[0318] In some embodiments, the VH of the anti-G6B antibody or binding fragment thereof further comprises a heavy chain complementarity determining region 2 (HC CDR2) of any one of the sequences selected from the group consisting of SEQ ID NOs: 203, 207, 210, 214, 218, 222, and 226. In some embodiments, the VH of the anti-G6B antibody or binding fragment thereof comprises a heavy chain complementarity determining region 2 (HC CDR2) of any one of the sequences selected from the group consisting of SEQ ID NOs: 203, 207, 210, 214, 218, 222, and 226. In some embodiments, the VH of the anti-G6B antibody or binding fragment thereof comprises a HC CDR2 comprising an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to any one of the sequences selected from the group consisting of SEQ ID NOs: 203, 207, 210, 214, 218, 222, and 226. In some embodiments, the VH of the anti-G6B antibody or binding fragment thereof comprises a HC CDR2 of any one of the HC CDR2 sequences listed in Table 3. In some embodiments, the VH of the anti-G6B antibody or binding fragment thereof comprises a HC CDR2 comprising an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to any one of the HC CDR2 sequences listed in Table 3.

[0319] In some embodiments, the anti-G6B antibody or binding fragment thereof comprises a light chainvariable domain (VL) comprising a light chain complementarity determining region 3 (LC CDR3) of any one of the sequences selected from the group consisting of SEQ ID NOs: 231, 235, 239, 243, 247, 250, 254, 258, 262, 266, 270, 274, and 278. In some embodiments, the anti-G6B antibody or binding fragment thereof comprises a VL comprising a LC CDR3 comprising an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to any one of the sequences selected from the group consisting of SEQ ID NOs: 231, 235, 239, 243, 247, 250, 254, 258, 262, 266, 270, 274, and 278. In some embodiments, the anti-G6B antibody or binding fragment thereof comprises a VL comprising a LC CDR3 of any one of the LC CDR3 sequences listed in Table 3. In some embodiments, the anti-G6B antibody or binding fragment thereof comprises a VL comprising a LC CDR3 comprising an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to any one of the LC CDR3 sequences listed in Table 3.

[0320] In some embodiments, the VL of the anti-G6B antibody or binding fragment thereof further comprises a light chain complementarity determining region 1 (LC CDR1) of any one of the sequences selected from the group consisting of SEQ ID NOs: 229, 233, 237, 241, 245, 252, 256, 260, 264, 268, 272, and 276. In some embodiments, the VL of the anti-G6B antibody or binding fragment thereof comprises a LC CDR1 comprising an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to any one of the sequences selected from the group consisting of SEQ ID NOs: 229, 233, 237, 241, 245, 252, 256, 260, 264, 268, 272, and 276. In some embodiments, the VL of the anti-G6B antibody or binding fragment thereof comprises a LC CDR1 of any one of the LC CDR1 sequences listed in Table 3. In some embodiments, the VL of the anti-G6B antibody or binding fragment thereof comprises a LC CDR1 comprising an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to any one of the LC CDR1 sequences listed in Table 3.

[0321] In some embodiments, the VL of the anti-G6B antibody or binding fragment thereof further comprises light chain complementarity determining region 2 (LC CDR2) of any one of the sequences selected from the group consisting of SEQ ID NOs: 230, 234, 238, 242, 246, 249, 253, 257, 261, 265, 269, 273, and 277. In some embodiments, the VL of the anti-G6B antibody or binding fragment thereof comprises a LC CDR2 comprising an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to any one of the sequences selected from the group consisting of SEQ ID NOs: 230, 234, 238, 242, 246, 249, 253, 257, 261, 265, 269, 273, and 277. In some embodiments, the VL of the anti-G6B antibody or binding fragment thereof comprises a LC CDR2 of any one of the LC CDR2 sequences listed in Table 3. In some embodiments, the VL of the anti-G6B antibody or binding fragment thereof comprises a LC CDR2 comprising an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to any one of the LC CDR2 sequences listed in Table 3.

[0322] In some embodiments, the anti-G6B antibody or binding fragment thereof comprises: (i) the VH comprising the HC CDR1 of any one of the sequences selected from the group consisting of SEQ ID NOs: 202, 206, 213, 217, 221, and 225, the HC CDR2 of any one of the sequences selected from the group consisting of SEQ ID NOs: 203, 207, 210, 214, 218, 222, and 226, and the HC CDR3 of any one of the sequences selected from the group consisting of SEQ ID NOs: 204, 208, 211, 215, 219, 223, and 227; (ii) the VL comprising the LC CDR1 of any one of the sequences selected from the group consisting of SEQ ID NOs: 229, 233, 237, 241, 245, 252, 256, 260, 264, 268, 272, and 276, the LC CDR2 of any one of the sequences selected from the group consisting of SEQ ID NOs: 230, 234, 238, 242, 246, 249, 253, 257, 261, 265, 269, 273, and 277, and the LC CDR3 of any one of the sequences selected from the group consisting of SEQ ID NOs: 231, 235, 239, 243, 247, 250, 254, 258, 262, 266, 270, 274, and 278; or (iii) any combination thereof. In some embodiments, the anti-G6B antibody or binding fragment thereof comprises: (i) the VH comprising the HC CDR1 comprising an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to any one of the sequences selected from the group consisting of SEQ ID NOs: 202, 206, 213, 217, 221, and 225, the HC CDR2 comprising an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to any one of the sequences selected from the group consisting of SEQ ID NOs: 203, 207, 210, 214, 218, 222, and 226, and the HC CDR3 comprising an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to any one of the sequences selected from the group consisting of SEQ ID NOs: 204, 208, 211, 215, 219, 223, and 227; (ii) the VL comprising the LC CDR1 comprising an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to any one of the sequences selected from the group consisting of SEQ ID NOs: 229, 233, 237, 241, 245, 252, 256, 260, 264, 268, 272, and 276, the LC CDR2 comprising an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to any one of the sequences selected from the group consisting of SEQ ID NOs: 230, 234, 238, 242, 246, 249, 253, 257, 261, 265, 269, 273, and 277, and the LC CDR3 comprising an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to any one of the sequences selected from the group consisting of SEQ ID NOs: 231, 235, 239, 243, 247, 250, 254, 258, 262, 266, 270, 274, and 278; or (iii) any combination thereof. In some embodiments, the anti-G6B antibody or binding fragment thereof comprises: (i) the VH comprising the HC CDR1 of any one of the HC CDR1 sequences listed in Table 3, the HC CDR2 of any one of the HC CDR2 sequences listed in Table 3, and the HC CDR3 of any one of the HC CDR3 sequences listed in Table 3; (ii) the VL comprising the LC CDR1 of any one of the LC CDR1 sequences listed in Table 3, the LC CDR2 of any one of the LC CDR1 sequences listed in Table 3, and the LC CDR3 of any one of the LC CDR1 sequences listed in Table 3; or (iii) any combination thereof. In some embodiments, the anti-G6B antibody or binding fragment thereof comprises: (i) the VH comprising the HCCDR1 comprising an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to any one of the HC CDR1 sequences listed in Table 3, the HC CDR2 comprising an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to any one of the HC CDR2 sequences listed in Table 3, and the HC CDR3 comprising an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to any one of the HC CDR3 sequences listed in Table 3; (ii) the VL comprising the LC CDR1 comprising an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to any one of the LC CDR1 sequences listed in Table 3, the LC CDR2 comprising an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to any one of the LC CDR2 sequences listed in Table 3, and the LC CDR3 comprising an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to any one of the LC CDR3 sequences listed in Table 3; or (iii) any combination thereof.

[0323] In some embodiments, the anti-G6B antibody or binding fragment thereof comprises: (i) the VH comprising a HC CDR1, a HC CDR2 and a HC CDR3 of SEQ ID NOs: 202, 203, and 204, respectively; SEQ ID NOs: 206, 207, and 208, respectively; SEQ ID NOs: 206, 210, and 211, respectively; SEQ ID NOs: 213, 214, and 215, respectively; SEQ ID NOs: 217, 218, and 219, respectively; SEQ ID NOs: 221, 222, and 223, respectively; or SEQ ID NOs: 225, 226, and 227, respectively; (ii) the VL comprising a LC CDR1, a LC CDR2 and a LC CDR3 of SEQ ID NOs: 229, 230, and 231, respectively; SEQ ID NOs: 233, 234, and 235, respectively; SEQ ID NOs: 237, 238, and 239, respectively; SEQ ID NOs: 241, 242, and 243, respectively; SEQ ID NOs: 245, 246, and 247, respectively; SEQ ID NOs: 245, 249, and 250, respectively; SEQ ID NOs: 252, 253, and 254, respectively; SEQ ID NOs: 256, 257, and 258, respectively; SEQ ID NOs: 260, 261, and 262, respectively; SEQ ID NOs: 264, 265, and 266, respectively; SEQ ID NOs: 268, 269, and 270, respectively; SEQ ID NOs: 272, 273, and 274, respectively; or SEQ ID NOs: 276, 277, and 278, respectively; or (iii) any combination thereof.

[0324] In some embodiments, the anti-G6B antibody or binding fragment thereof comprises: (i) a VH comprising an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 201, 205, 209, 212, 216, 220, and 224; (ii) a VL comprising an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 228, 232, 236, 240, 244, 248, 251, 255, 259, 263, 267, 271, and 275; or (iii) any combination thereof. In some embodiments, the anti-G6B antibody or binding fragment thereof comprises: (i) a VH comprising a sequence selected from the group consisting of SEQ ID NOs: 201, 205, 209, 212, 216, 220, and 224; (ii) a VL comprising a sequence selected from the group consisting of SEQ ID NOs: 228, 232, 236, 240, 244, 248,251, 255, 259, 263, 267, 271, and 275; or (iii) any combination thereof. In some embodiments, the anti-G6B antibody or binding fragment thereof comprises: (i) a VH of any one of the sequences of SEQ ID NOs: 201, 205, 209, 212, 216, 220, and 224; (ii) a VL of any one of the sequences of SEQ ID NOs: 228, 232, 236, 240, 244, 248, 251, 255, 259, 263, 267, 271, and 275; or (iii) any combination thereof. In some embodiments, the anti-G6B antibody or binding fragment thereof comprises: (i) a VH comprising an ammo acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to a VH sequence listed in Table 3; (ii) a VL comprising an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to a VL sequence listed in Table 3; or (iii) any combination thereof. In some embodiments, the anti-G6B antibody or binding fragment thereof comprises: (i) a VH comprising a VH sequence listed in Table 3; (ii) a VL comprising a VL sequence listed in Table 3; or (iii) any combination thereof. In some embodiments, the anti-G6B antibody or binding fragment thereof comprises: (i) a VH of any one of a VH sequence listed in Table 3; (ii) a VL of any one of a VL sequence listed in Table 3; or (iii) any combination thereof.

[0325] In some embodiments, the anti-G6B antibody or binding fragment thereof comprises: a VH of SEQ ID NO: 201 and a VL of SEQ ID NO: 228; a VH of SEQ ID NO: 201 and aVL of SEQ ID NO: 232; a VH of SEQ ID NO : 201 and a VL of SEQ ID NO : 236; a VH of SEQ ID NO : 201 and a VL of SEQ ID NO : 240; a VH of SEQ ID NO: 201 and a VL of SEQ ID NO: 244; a VH of SEQ ID NO: 201 and a VL of SEQ ID NO: 248; a VH of SEQ ID NO: 201 and a VL of SEQ ID NO: 251; a VH of SEQ ID NO: 201 and a VL of SEQ ID NO : 255 ; a VH of SEQ ID NO : 201 and a VL of SEQ ID NO : 259; a VH of SEQ ID NO : 201 and a VL of SEQ ID NO: 263; a VH of SEQ ID NO: 201 and aVL of SEQ ID NO: 267; a VH of SEQ ID NO : 201 and a VL of SEQ ID NO : 271 ; a VH of SEQ ID NO : 201 and a VL of SEQ ID NO : 275 ; a VH of SEQ ID NO: 205 and a VL of SEQ ID NO: 228; a VH of SEQ ID NO: 205 and a VL of SEQ ID NO: 232; a VH of SEQ ID NO: 205 and a VL of SEQ ID NO: 236; a VH of SEQ ID NO: 205 and a VL of SEQ ID NO: 240; a VH of SEQ ID NO: 205 and a VL of SEQ ID NO: 244; a VH of SEQ ID NO: 205 and a VL of SEQ ID NO: 248; a VH of SEQ ID NO: 205 and a VL of SEQ ID NO: 251; a VH of SEQ ID NO: 205 and a VL of SEQ ID NO: 255; a VH of SEQ ID NO: 205 and a VL of SEQ ID NO: 259; a VH of SEQ ID NO: 205 and a VL of SEQ ID NO: 263; a VH of SEQ ID NO: 205 and a VL of SEQ ID NO: 267; a VH of SEQ ID NO : 205 and a VL of SEQ ID NO : 271 ; a VH of SEQ ID NO : 205 and a VL of SEQ ID NO : 275 ; a VH of SEQ ID NO: 209 and a VL of SEQ ID NO: 228; a VH of SEQ ID NO: 209 and a VL of SEQ ID NO: 232; a VH of SEQ ID NO: 209 and a VL of SEQ ID NO: 236; a VH of SEQ ID NO: 209 and a VL of SEQ ID NO: 240; a VH of SEQ ID NO: 209 and a VL of SEQ ID NO: 244; a VH of SEQ ID NO: 209 and a VL of SEQ ID NO: 248; a VH of SEQ ID NO: 209 and a VL of SEQ ID NO: 251; a VH of SEQ ID NO: 209 and a VL of SEQ ID NO: 255; a VH of SEQ ID NO: 209 and a VL of SEQ ID NO: 259; a VH of SEQ ID NO: 209 and a VL of SEQ ID NO: 263; a VH of SEQ ID NO: 209 and a VL of SEQ ID NO: 267; a VH of SEQ ID NO : 209 and a VL of SEQ ID NO : 271 ; a VH of SEQ ID NO : 209 and a VL of SEQ ID NO : 275 ; a VH of SEQ ID NO: 212 and a VL of SEQ ID NO: 228; a VH of SEQ ID NO: 212 and a VL of SEQ ID NO: 232; aVH of SEQ ID NO: 212 and a VL of SEQ ID NO: 236; a VH of SEQ ID NO: 212 and a VL of SEQ ID NO: 240; a VH of SEQ ID NO: 212 and a VL of SEQ ID NO: 244; a VH of SEQ ID NO: 212 and a VL of SEQ ID NO: 248; a VH of SEQ ID NO: 212 and a VL of SEQ ID NO: 251; a VH of SEQ ID NO: 212 and a VL of SEQ ID NO: 255; a VH of SEQ ID NO: 212 and a VL of SEQ ID NO: 259; a VH of SEQ ID NO: 212 and a VL of SEQ ID NO: 263; a VH of SEQ ID NO: 212 and a VL of SEQ ID NO: 267; a VH of SEQ ID NO : 212 and a VL of SEQ ID NO : 271 ; a VH of SEQ ID NO : 212 and a VL of SEQ ID NO : 275 ; a VH of SEQ ID NO: 216 and a VL of SEQ ID NO: 228; a VH of SEQ ID NO: 216 and a VL of SEQ ID NO: 232; a VH of SEQ ID NO : 216 and a VL of SEQ ID NO : 236; a VH of SEQ ID NO : 216 and a VL of SEQ ID NO : 240; a VH of SEQ ID NO: 216 and a VL of SEQ ID NO: 244; a VH of SEQ ID NO: 216 and a VL of SEQ ID NO: 248; a VH of SEQ ID NO: 216 and a VL of SEQ ID NO: 251; a VH of SEQ ID NO: 216 and a VL of SEQ ID NO: 255; a VH of SEQ ID NO: 216 and a VL of SEQ ID NO: 259; a VH of SEQ ID NO: 216 and a VL of SEQ ID NO: 263; a VH of SEQ ID NO: 216 and a VL of SEQ ID NO: 267; a VH of SEQ ID NO : 216 and a VL of SEQ ID NO : 271 ; a VH of SEQ ID NO : 216 and a VL of SEQ ID NO : 275 ; a VH of SEQ ID NO: 220 and a VL of SEQ ID NO: 228; a VH of SEQ ID NO: 220 and a VL of SEQ ID NO: 232; a VH of SEQ ID NO: 220 and a VL of SEQ ID NO: 236; a VH of SEQ ID NO: 220 and a VL of SEQ ID NO: 240; a VH of SEQ ID NO: 220 and a VL of SEQ ID NO: 244; a VH of SEQ ID NO: 220 and a VL of SEQ ID NO: 248; a VH of SEQ ID NO: 220 and a VL of SEQ ID NO: 251; a VH of SEQ ID NO: 220 and a VL of SEQ ID NO: 255; a VH of SEQ ID NO: 220 and a VL of SEQ ID NO: 259; a VH of SEQ ID NO: 220 and a VL of SEQ ID NO: 263; a VH of SEQ ID NO: 220 and a VL of SEQ ID NO: 267; a VH of SEQ ID NO : 220 and a VL of SEQ ID NO : 271 ; a VH of SEQ ID NO : 220 and a VL of SEQ ID NO : 275 ; a VH of SEQ ID NO: 224 and a VL of SEQ ID NO: 228; a VH of SEQ ID NO: 224 and a VL of SEQ ID NO: 232; a VH of SEQ ID NO: 224 and a VL of SEQ ID NO: 236; a VH of SEQ ID NO: 224 and a VL of SEQ ID NO: 240; a VH of SEQ ID NO: 224 and a VL of SEQ ID NO: 244; a VH of SEQ ID NO: 224 and a VL of SEQ ID NO: 248; a VH of SEQ ID NO: 224 and a VL of SEQ ID NO: 251; a VH of SEQ ID NO: 224 and a VL of SEQ ID NO: 255; a VH of SEQ ID NO: 224 and a VL of SEQ ID NO: 259; a VH of SEQ ID NO: 224 and a VL of SEQ ID NO: 263; a VH of SEQ ID NO: 224 and a VL of SEQ ID NO: 267; a VH of SEQ ID NO: 224 and a VL of SEQ ID NO: 271; or a VH of SEQ ID NO: 224 and a VL of SEQ ID NO: 275.

[0326] In some embodiments, the VH of the anti-CD34 antibody or binding fragment thereof further comprises a heavy chain complementarity determining region 1 (HC CDR1) of SEQ ID NO: 281. In some embodiments, the VH of the anti-CD34 antibody or binding fragment thereof comprises a HC CDR1 comprising an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to the sequences of SEQ ID NO: 281. In some embodiments, the VH of the anti-CD34 antibody or binding fragment thereof comprises a HC CDR1 of any one of the HC CDR1 sequences listed in Table 4. In some embodiments, the VH of the anti- CD34 antibody or binding fragment thereof comprises a HC CDR1 comprising an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to any one of the HC CDR1 sequences listed in Table 4.

[0327] In some embodiments, the VH of the anti-CD34 antibody or binding fragment thereof further comprises a heavy chain complementarity determining region 2 (HC CDR2) of SEQ ID NO: 280. In some embodiments, the VH of the anti-CD34 antibody or binding fragment thereof comprises a HC CDR2 comprising an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to the sequences of SEQ ID NO: 280. In some embodiments, the VH of the anti-CD34 antibody or binding fragment thereof comprises a HC CDR2 of any one of the HC CDR2 sequences listed in Table 4. In some embodiments, the VH of the anti- CD34 antibody or binding fragment thereof comprises a HC CDR2 comprising an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to any one of the HC CDR2 sequences listed in Table 4.

[0328] In some embodiments, the anti-CD34 antibody or binding fragment thereof comprises a light chain variable domain (VL) comprising a light chain complementarity determining region 3 (LC CDR3) of SEQ ID NO: 291. In some embodiments, the anti-CD34 antibody or binding fragment thereof comprises a VL comprising a LC CDR3 comprising an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to the sequences of SEQ ID NO: 291. In some embodiments, the anti-CD34 antibody or binding fragment thereof comprises a VL comprising a LC CDR3 of any one of the LC CDR3 sequences listed in Table 4. In some embodiments, the anti-CD34 antibody or binding fragment thereof comprises a VL comprising a LC CDR3 comprising an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to any one of the LC CDR3 sequences listed in Table 4.

[0329] In some embodiments, the VL of the anti-CD34 antibody or binding fragment thereof further comprises a light chain complementarity determining region 1 (LC CDR1) of SEQ ID NO: 290. In some embodiments, the VL of the anti-CD34 antibody or binding fragment thereof comprises a LC CDR1 comprising an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to the sequences of SEQ ID NO: 290. In some embodiments, the VL of the anti-CD34 antibody or binding fragment thereof comprises a LC CDR1 of any one of the LC CDR1 sequences listed in Table 4. In some embodiments, the VL of the anti- CD34 or binding fragment thereof comprises a LC CDR1 comprising an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to any one of the LC CDR1 sequences listed in Table 4.

[0330] In some embodiments, the VL of the anti-CD34 antibody or binding fragment thereof further comprises light chain complementarity determining region 2 (LC CDR2) of SEQ ID NO: 289. In some embodiments, the VL of the anti-CD34 antibody or binding fragment thereof comprises a LC CDR2 comprising an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to the sequences of SEQ ID NO: 289. In some embodiments, the VL of the anti-CD34 antibody or binding fragment thereof comprises a LCCDR2 of any one of the LC CDR2 sequences listed in Table 4. In some embodiments, the VL of the anti- CD34 or binding fragment thereof comprises a LC CDR2 comprising an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to any one of the LC CDR2 sequences listed in Table 4.

[0331] In some embodiments, the anti-CD34 antibody or binding fragment thereof comprises: (i) the VH comprising the HC CDR1 of SEQ ID NO: 280, the HC CDR2 of SEQ ID NO: 281, and the HC CDR3 of SEQ ID NO: 282; (ii) the VL comprising the LC CDR1 of SEQ ID NO: 289, the LC CDR2 of SEQ ID NO: 290, and the LC CDR3 of SEQ ID NO: 291; or (iii) any combination thereof.

[0332] In some embodiments, the anti-CD34 antibody or binding fragment thereof comprises: (i) the VH comprising the HC CDR1 comprising an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to the sequence of SEQ ID NO: 280, the HC CDR2 comprising an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to the sequence of SEQ ID NO: 281, and the HC CDR3 comprising an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to the sequence of SEQ ID NO: 282; (ii) the VL comprising the LC CDR1 comprising an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to the sequence of SEQ ID NO: 289, the LC CDR2 comprising an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to the sequence of SEQ ID NO: 290, and the LC CDR3 comprising an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to the sequence of SEQ ID NO: 291; or (iii) any combination thereof. In some embodiments, the anti-CD34 antibody or binding fragment thereof comprises: (i) the VH comprising the HC CDR1 of any one of the HC CDR1 sequences listed in Table 4, the HC CDR2 of any one of the HC CDR2 sequences listed in Table 4, and the HC CDR3 of any one of the HC CDR3 sequences listed in Table 4; (ii) the VL comprising the LC CDR1 of any one of the LC CDR1 sequences listed in Table 4, the LC CDR2 of any one of the LC CDR2 sequences listed in Table 4, and the LC CDR3 of any one of the LC CDR3 sequences listed in Table 4; or (iii) any combination thereof.

[0333] In some embodiments, the anti-CD34 antibody or binding fragment thereof comprises: (i) the VH comprising the HC CDR1 comprising an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to any one of the HC CDR1 sequences listed in Table 4, the HC CDR2 comprising an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to any one of the HC CDR2 sequences listed in Table 4, and the HC CDR3 comprising an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to any one of the HC CDR3sequences listed in Table 4; (ii) the VL comprising the LC CDR1 comprising an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to any one of the LC CDR1 sequences listed in Table 4, the LC CDR2 comprising an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to any one of the LC CDR2 sequences listed in Table 4, and the LC CDR3 comprising an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to any one of the LC CDR3 sequences listed in Table 4; or (iii) any combination thereof.

[0334] In some embodiments, the anti-CD34 antibody or binding fragment thereof comprises: (i) a VH comprising an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 279, 283, 284, 285, 286, and 287; (ii) a VL comprising an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 288, 292, 293, and 294; or (iii) any combination thereof. In some embodiments, the anti-CD34 antibody or binding fragment thereof comprises: (i) a VH comprising a sequence selected from the group consisting of SEQ ID NOs: 279, 283, 284, 285, 286, and 287; (ii) a VL comprising a sequence selected from the group consisting of SEQ ID NOs: 288, 292, 293, and 294; or (iii) any combination thereof. In some embodiments, the anti-CD34 antibody or binding fragment thereof comprises: (i) a VH of any one of the sequence of SEQ ID NOs: 279, 283, 284, 285, 286, and 287; (ii) a VL of any one of the sequence of SEQ ID NOs: 288, 292, 293, and 294; or (iii) any combination thereof.

[0335] In some embodiments, the anti-CD34 antibody or binding fragment thereof comprises: (i) a VH comprising an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to a VH sequence listed in Table 4; (ii) a VL comprising an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to a VL sequence listed in Table 4; or (iii) any combination thereof. In some embodiments, the anti-CD34 antibody or binding fragment thereof comprises: (i) a VH comprising a VH sequence listed in Table 4; (ii) a VL comprising a VL sequence listed in Table 4; or (iii) any combination thereof. In some embodiments, the anti-CD34 antibody or binding fragment thereof comprises: (i) a VH of any one of a VH sequence listed in Table 4; (ii) a VL of any one of a VL sequence listed in Table 4; or (iii) any combination thereof.

[0336] In some embodiments, the anti-CD34 antibody or binding fragment thereof comprises: a VH of SEQ ID NO: 279 and a VL of SEQ ID NO: 292; a VH of SEQ ID NO: 279 and a VL of SEQ ID NO: 293; a VH of SEQ ID NO: 279 and a VL of SEQ ID NO: 294; a VH of SEQ ID NO: 283 and a VL of SEQ ID NO: 292; a VH of SEQ ID NO: 283 and a VL of SEQ ID NO: 293; a VH of SEQ ID NO: 283 and a VL of SEQ ID NO: 294; a VH of SEQ ID NO: 284 and a VL of SEQ ID NO: 292; a VH of SEQ ID NO: 284 and a VL of SEQ ID NO: 293; a VH of SEQ ID NO: 284 and a VL of SEQ ID NO: 294; a VH of SEQ ID NO: 285and a VL of SEQ ID NO: 292; a VH of SEQ ID NO: 285 and a VL of SEQ ID NO: 293; a VH of SEQ ID NO: 285 and a VL of SEQ ID NO: 294; a VH of SEQ ID NO: 286 and a VL of SEQ ID NO: 292; a VH of SEQ ID NO: 286 and a VL of SEQ ID NO: 293; a VH of SEQ ID NO: 286 and a VL of SEQ ID NO: 294; a VH of SEQ ID NO: 287 and a VL of SEQ ID NO: 292; a VH of SEQ ID NO: 287 and a VL of SEQ ID NO: 293; or a VH of SEQ ID NO: 287 and a VL of SEQ ID NO: 294.

[0337] In some embodiments, the multifunctional molecule comprises an anti-G6B antibody or binding fragment thereof as provided herein linked to an antigen binding moiety. In some embodiments, the antigen binding moiety is an anti-CD34 antibody or binding fragm ent thereof as provided herein.

[0338] In some embodiments, the multifunctional molecule comprises an anti-CD34 antibody or binding fragment thereof as provided herein linked to an antigen binding moiety. In some embodiments, the antigen binding moiety is an anti-G6B antibody or binding fragment thereof as provided herein.

[0339] In some embodiments, the multifunctional molecule further comprises: (i) a constant heavy chain 1 domain (CHI) linked to the VH of anti-G6B antibody or binding fragment thereof, a CHI linked to the VH of the anti-CD34 antibody or binding fragment thereof, or any combination thereof; (ii) a constant light chain domain (CL) linked to the VL of the anti-G6B antibody or binding fragment thereof, a CL linked to the VL of the anti-CD34 antibody or binding fragment thereof, or any combination thereof; or (iii) any combination thereof. In some embodiments, the CHI linked to the VH of anti-G6B antibody or binding fragment thereof and the CHI linked to the VH of the anti-CD34 antibody or binding fragment thereof are independently a CHI of IgGl, IgG2, IgG3, IgGAl, IgGA2, IgG4, IgJ, IgM, IgD, or IgE. In some embodiments, the CHI linked to the VH of anti-G6B antibody or binding fragment thereof and the CHI linked to the VH of the anti-CD34 antibody or binding fragment thereof independently comprise any one of the CHI sequences selected from the group consisting of SEQ ID NOs: 299, 300, and 302-309. In some embodiments, the CHI linked to the VH of anti-G6B antibody or binding fragment thereof and the CHI linked to the VH of the anti-CD34 antibody or binding fragment thereof independently comprise an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to any one of the CHI sequences selected from the group consisting of SEQ ID NOs: 299, 300, and 302-309.

[0340] In some embodiments, the CL linked to the VL of the anti-G6B antibody or binding fragment thereof and the CL linked to the VL of the anti-CD34 antibody or binding fragment thereof are independently a CL of a lambda light chain or a CL of a kappa light chain. In some embodiments, the CL linked to the VL of the anti-G6B antibody or binding fragment thereof and the CL linked to the VL of the anti-CD34 antibody or binding fragment thereof independently comprise any one of the sequences selected from the group consisting of SEQ ID NOs: 297 and 298. In some embodiments, the CL linked to the VL of the anti-G6B antibody or binding fragment thereof and the CL linked to the VL of the anti-CD34 antibody or binding fragment thereof independently comprise an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to any one of the sequences selected from the group consisting of SEQ ID NOs: 297 and 298.

[0341] In some embodiments, the CHI linked to the VH of anti-G6B antibody or binding fragment thereof and the CHI linked to the VH of the anti-CD34 antibody or binding fragment thereof independently comprise any one of the CHI sequences listed in Table 5. In some embodiments, the CHI linked to the VH of anti-G6B antibody or binding fragment thereof and the CHI linked to the VH of the anti-CD34 antibody or binding fragment thereof independently comprise an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to any one of the CHI sequences listed in Table 5.

[0342] In some embodiments, the CL linked to the VL of the anti-G6B antibody or binding fragment thereof and the CL linked to the VL of the anti-CD34 antibody or binding fragment thereof independently comprise any one of the CL sequences listed in Table 5. In some embodiments, the CL linked to the VL of the anti-G6B antibody or binding fragment thereof and the CL linked to the VL of the anti-CD34 antibody or binding fragment thereof independently comprise an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to any one of the CL sequences listed in Table 5.

[0343] In some embodiments, the anti-G6B antibody or binding fragment thereof and the anti-CD34 antibody or binding fragment thereof is covalently linked or non-covalently linked.

[0344] In some embodiments, the multifunctional molecule comprises a first polypeptide comprising (i) the anti-G6B antibody or binding fragment thereof linked to the anti-CD34 antibody or binding fragment thereof; (ii) a first portion of the anti-G6B antibody or binding fragment thereof linked to a first portion of the anti-CD34 antibody or binding fragment thereof, wherein the multifunctional molecule further comprises a second polypeptid e compri sing a second portion of the anti-G6B antibody or binding fragment thereof and a third polypeptide comprising a second portion of the anti-CD34 antibody or binding fragment thereof; (iii) a first portion of the anti-G6B antibody or binding fragment thereof linked to the anti-CD34 antibody or binding fragment thereof, wherein the multifunctional molecule further comprises a second polypeptide comprising a second portion of the anti-G6B antibody or binding fragment thereof; or (iv) the anti-G6B antibody or binding fragment thereof linked to a first portion of the anti-CD34 antibody or binding fragment thereof, wherein the multifunctional molecule further comprises a second polypeptide comprising a second portion of the anti-CD34 antibody or binding fragment thereof.

[0345] In some embodiments, the anti-G6B antibody or binding fragment thereof and the anti-CD34 antibody or binding fragment thereof, the first portion of the anti-G6B antibody or binding fragment thereof and the first portion of the anti-CD34 antibody or binding fragment thereof, the first portion of the anti-G6B antibody or binding fragment thereof and the anti-CD34 antibody or binding fragment thereof, or the anti- G6B antibody or binding fragment thereof and the first portion of the anti-CD34 antibody or binding fragment thereof are independently linked by a linker.

[0346] In some embodiments, the multifunctional molecule as provided herein is a multispecific molecule.Multifunctional Molecules Comprising Dimerization Module 00347] In some embodiments, the multifunctional molecule comprises at least two non-contiguous polypeptide chains.

[0348] In some embodiments, a first polypeptide comprises a first member of a dimerization module and a second polypeptide comprises a second member of the dimerization module, wherein the first polypeptide and the second polypeptide form a complex via the first member of the dimerization module and the second member of the dimerization module.

[0349] In some embodiments, the first member of the dimerization module is a first Fc region, and the second member of the dimerization module is a second Fc region.

[0350] In some embodiments, the first Fc region and the second Fc region are independently an IgGl Fc region or fragment thereof, an IgG2 Fc region or fragment thereof, an IgG3 Fc region or fragment thereof, an IgGAl Fc region or fragment thereof, an IgGA2 Fc region or fragment thereof, an IgG4 Fc region or fragment thereof, an IgJ Fc region or fragment thereof, an IgM Fc region or fragment thereof, an IgD Fc region or fragment thereof, or an IgE Fc region or fragment thereof.

[0351] In some embodiments, the first Fc region and the second Fc region independently comprise any one of the Fc sequences selected from the group consisting of SEQ ID NOs: 302-307. In some embodiments, the first Fc region and the second Fc region independently comprise an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to any one of the Fc sequences selected from the group consisting of SEQ ID NOs: 302-307.

[0352] In some embodiments, the first Fc region is an engineered first Fc region comprising a knob and the second Fc region is an engineered second Fc region comprising a hole, or wherein the first Fc region is an engineered first Fc region comprising a hole and the second Fc region is an engineered second Fc region comprising a knob.

[0353] In some embodiments, the engineered first Fc region comprises the sequence of SEQ ID NO: 310 or SEQ ID NO: 312 and the engineered second Fc region comprises the sequence of SEQ ID NO: 311 or SEQ ID NO: 313, or wherein the engineered first Fc region comprises the sequence of SEQ ID NO: 311 or SEQ ID NO: 313 and the engineered second Fc region comprises the sequence of SEQ ID NO: 310 or SEQ ID NO: 312. In some embodiments, the engineered first Fc region comprises an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to the sequence of SEQ ID NO: 310 or SEQ ID NO: 312 and the engineered second Fc region comprises an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to the sequence of SEQ ID NO: 311 or SEQ ID NO: 313, or wherein the engineered first Fc region comprises an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to the sequence of SEQ ID NO: 311 or SEQ ID NO: 313 and the engineered second Fc region comprises an amino acid sequence with at least 50%, 55%, 60%, 65%,70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to the sequence of SEQ ID NO: 310 or SEQ ID NO: 312.

[0354] In some embodiments, the first Fc region and the second Fc region independently comprise any one of the Fc sequences listed in Table 5. In some embodiments, the first Fc region and the second Fc region independently comprise an amino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, 99.9% sequence identity to any one of the Fc sequences listed in Table 5.

[0355] Fc-containing multispecific molecules

[0356] In some embodiments, the multifunctional molecules as provided herein are multispecific molecules. In some embodiments, the multispecific molecules disclosed herein includes an immunoglobulin constant region (e.g., an Fc region). Exemplary Fc regions can be selected from the heavy chain constant regions of IgGl, IgG2, IgG3 and IgG4; more particularly, the heavy chain constant region of human IgGl, IgG2, IgG3, and IgG4.

[0357] In some embodiments, the immunoglobulin chain constant region (e.g., the Fc region) is altered, e.g., mutated, to increase or decrease one or more of: Fc receptor binding, antibody glycosylation, the number of cysteine residues, effector cell function, or complement function.

[0358] In other embodiments, an interface of a first and second immunoglobulin chain constant regions (e.g., a first and a second Fc region) is altered, e.g., mutated, to increase or decrease dimerization, e.g., relative to a non-engineered interface, e.g., a naturally-occurring interface. For example, dimerization of the immunoglobulin chain constant region (e.g., the Fc region) can be enhanced by providing an Fc interface of a first and a second Fc region with one or more of: a paired protuberance-cavity (“knob-in-a hole”), an electrostatic interaction, or a strand-exchange, such that a greater ratio of heteromultimer to homomultimer forms, e.g., relative to a non-engineered interface.

[0359] In some embodiments, the multispecific molecules include a paired amino acid substitution at a position selected from one or more of 347, 349, 350, 351, 366, 368, 370, 392, 394, 395, 397, 398, 399, 405, 407, and 409, e.g., of the Fc region of human IgGl. For example, the immunoglobulin chain constant region (e.g., Fc region) can include a paired an amino acid substitution selected from: T366S, L368A, Y407V (e.g., corresponding to a cavity or hole), and T366W (e.g., corresponding to a protuberance or knob).

[0360] In other embodiments, the multifunctional molecule includes a half-life extender, e.g., a human serum albumin or an antibody molecule to human serum albumin.

[0361] Heterodimerized Antibody Molecules & Methods of Making

[0362] Various methods of producing multispecific antibodies have been disclosed to address the problem of incorrect heavy chain pairing. Exemplary methods are described below. Exemplary multispecific antibody formats and methods of making said multispecific antibodies are also disclosed in e.g., Speiss et al. Molecular Immunology 67 (2015) 95-106; and Klein et al mAbs 4:6, 653-663; November / December 2012;the entire contents of each of which are incorporated by reference herein.

[0363] Heterodimerized bispecific antibodies are based on the natural IgG structure, wherein the two binding arms recognize different antigens. IgG derived formats that enable defined monovalent (and simultaneous) antigen binding are generated by forced heavy chain heterodimerization, combined with technologies that minimize light chain mispairing (e.g., common light chain). Forced heavy chain heterodimerization can be obtained using, e.g., knob-in-hole OR strand exchange engineered domains (SEED).

[0364] Knob-in-Hole

[0365] Knob-in-Hole as described in US 5,731,116, US 7,476,724 and Ridgway, J. et al. (1996) Prot. Engineering 9(7): 617-621, broadly involves: (1) mutating the CH3 domain of one or both antibodies to promote heterodimerization; and (2) combining the mutated antibodies under conditions that promote heterodimerization. “Knobs” or “protuberances” are typically created by replacing a small amino acid in a parental antibody with a larger amino acid (e.g., T366Y or T366W); “Holes” or “cavities” are created by replacing a larger residue in a parental antibody with a smaller amino acid (e.g., Y407T, T366S, L368A and / or Y407V).

[0366] For bispecific antibodies including an Fc domain, introduction of specific mutations into the constant region of the heavy chains to promote the correct heterodimerization of the Fc portion can be utilized. Several such techniques are reviewed in Klein et al. (mAbs (2012) 4:6, 1-11), the contents of which are incorporated herein by reference in their entirety. These techniques include the "knobs-into-holes" (KiH) approach which involves the introduction of a bulky residue into one of the CH3 domains of one of the antibody heavy chains. This bulky residue fits into a complementary "hole" in the other CH3 domain of the paired heavy chain so as to promote correct pairing of heavy chains (see e.g., US7642228).

[0367] Exemplary KiH mutations include S354C, T366W in the “knob” heavy chain and Y349C, T366S, L368A, Y407V in the “hole” heavy chain. Other exemplary KiH mutations are provided in Table 1, with additional optional stabilizing Fc cysteine mutations.Table 1. Exemplary Fc KiH mutations and optional Cysteine mutations

[0368] Other Fc mutations are provided by Igawa and Tsunoda who identified 3 negatively charged residues in the CH3 domain of one chain that pair with three positively charged residues in the CH3 domain of the other chain. These specific charged residue pairs are: E356-K439, E357-K370, D399-K409 and viceversa. By introducing at least two of the following three mutations in chain A: E356K, E357K and D399K, as well as K370E, K409D, K439E in chain B, alone or in combination with newly identified disulfide bridges, they were able to favor very efficient heterodimerization while suppressing homodimerization at the same time (Martens T et al. A novel one-armed antic- Met antibody inhibits glioblastoma growth in vivo. Clin Cancer Res 2006; 12:6144-52; PMID: 17062691). Xencor defined 41 variant pairs based on combining structural calculations and sequence information that were subsequently screened for maximal heterodimerization, defining the combination of S364H, F405A (HA) on chain A and Y349T, T394F on chain B (TF) (Moore GL et al. A novel bispecific antibody format enables simultaneous bivalent and monovalent co-engagement of distinct target antigens. MAbs 2011; 3:546-57; PMID: 22123055).

[0369] Other exemplary Fc mutations to promote heterodimerization of multispecific antibodies include those described in the following references, the contents of each of which is incorporated by reference herein, WO2016071377A1, US20140079689A1, US20160194389A1, US20160257763, WO2016071376A2, W02015107026A1, W02015107025A1, W02015107015A1, US20150353636A1, US20140199294A1, US7750128B2, US20160229915A1, US20150344570A1, US8003774A1, US20150337049A1, US20150175707A1, US20140242075A1, US20130195849A1, US20120149876A1, US20140200331A1, US9309311B2, US8586713, US20140037621A1, US20130178605A1, US20I40363426AI, US20I4005I835AI and US20110054151A1.

[0370] Stabilizing cysteine mutations have also been used in combination with KiH and other Fc heterodimerization promoting variants, see e.g., US7183076. Other exemplary cysteine modifications include, e.g., those disclosed in US20140348839A1, US7855275B2, and US9000130B2.

[0371] Strand Exchange Engineered Domains (SEED)

[0372] Heterodimeric Fc platform that support the design of bispecific and asymmetric fusion proteins by devising strand-exchange engineered domain (SEED) C(H)3 heterodimers are known. These derivatives of human IgG and IgA C(H)3 domains create complementary human SEED C(H)3 heterodimers that are composed of alternating segments of human IgA and IgG C(H)3 sequences. The resulting pair of SEED C(H)3 domains preferentially associates to form heterodimers when expressed in mammalian cells. SEEDbody (Sb) fusion proteins consist of [IgGl hinge] -C(H)2-[SEED C(H)3], that may be genetically linked to one or more fusion partners (see e.g., Davis JH et al. SEEDbodies: fusion proteins based on strand exchange engineered domain (SEED) CH3 heterodimers in an Fc analogue platform for asymmetric binders or immunofiisions and bispecific antibodies. Protein Eng Des Sei 2010; 23: 195-202; PMID:20299542 and US8871912. The contents of each of which are incorporated by reference herein).

[0373] Duobody

[0374] “Duobody” technology to produce bispecific antibodies with correct heavy chain pairing are known. The DuoBody technology involves three basic steps to generate stable bispecific human IgGl antibodies in a post-production exchange reaction. In a first step, two IgG Is, each containing singlematched mutations in the third constant (CH3) domain, are produced separately using standard mammalian recombinant cell lines. Subsequently, these IgGl antibodies are purified according to standard processes for recovery and purification. After production and purification (post-production), the two antibodies are recombined under tailored laboratory conditions resulting in a bispecific antibody product with a very high yield (typically >95%) (see e.g., Labrijn et al, PNAS 2013; 110(13):5145-5150 and Labrijn et al. Nature Protocols 2014;9(10):2450-63, the contents of each of which are incorporated by reference herein).

[0375] Electrostatic Interactions

[0376] Methods of making multispecific antibodies using CH3 amino acid changes with charged amino acids such that homodimer formation is electrostatically unfavorable are disclosed. EP1870459 and WO 2009089004 describe other strategies for favoring heterodimer formation upon co-expression of different antibody domains in a host cell. In these methods, one or more residues that make up the heavy chain constant domain 3 (CH3), CH3-CH3 interfaces in both CH3 domains are replaced with a charged amino acid such that homodimer formation is electrostatically unfavorable and heterodimerization is electrostatically favorable. Additional methods of making multispecific molecules using electrostatic interactions are described in the following references, the contents of each of which is incorporated by reference herein, include US20100015133, US8592562B2, US9200060B2, US20140154254A1, and US9358286A1.

[0377] Common Light Chain

[0378] Light chain mispairing needs to be avoided to generate homogenous preparations of bispecific IgGs. One way to achieve this is through the use of the common light chain principle, i.e. combining two binders that share one light chain but still have separate specificities. An exemplary method of enhancing the formation of a desired bispecific antibody from a mixture of monomers is by providing a common variable light chain to interact with each of the heteromeric variable heavy chain regions of the bispecific antibody. Compositions and methods of producing bispecific antibodies with a common light chain as disclosed in, e.g., US7183076B2, US20110177073A1, EP2847231A1, W02016079081A1, and EP3055329A1, the contents of each of which is incorporated by reference herein.

[0379] CrossMab

[0380] Another option to reduce light chain mispairing is the CrossMab technology which avoids nonspecific L chain mispairing by exchanging CHI and CL domains in the Lab of one half of the bispecific antibody. Such crossover variants retain binding specificity and affinity, but make the two arms so different that L chain mispairing is prevented. The CrossMab technology (as reviewed in Klein et al. Supra) involves domain swapping between heavy and light chains so as to promote the formation of the correct pairings. Briefly, to construct a bispecific IgG-like CrossMab antibody that could bind to two antigens by using two distinct light chain-heavy chain pairs, a two-step modification process is applied. Eirst, a dimerization interface is engineered into the C-terminus of each heavy chain using a heterodimerization approach, e.g.,Knob-into-hole (KiH) technology, to ensure that only a heterodimer of two distinct heavy chains from one antibody (e.g., Antibody A) and a second antibody (e.g., Antibody B) is efficiently formed. Next, the constant heavy 1 (CHI) and constant light (CL) domains of one antibody are exchanged (Antibody A), keeping the variable heavy (VH) and variable light (VL) domains consistent. The exchange of the CHI and CL domains ensured that the modified antibody (Antibody A) light chain would only efficiently dimerize with the modified antibody (antibody A) heavy chain, while the unmodified antibody (Antibody B) light chain would only efficiently dimerize with the unmodified antibody (Antibody B) heavy chain; and thus only the desired bispecific CrossMab would be efficiently formed (see e.g., Cain, C. SciBX 4(28); doi: 10.1038 / scibx.2011.783, the contents of which are incorporated by reference herein).

[0381] Common Heavy Chain

[0382] An exemplary method of enhancing the formation of a desired bispecific antibody from a mixture of monomers is by providing a common variable heavy chain to interact with each of the heteromeric variable light chain regions of the bispecific antibody. Compositions and methods of producing bispecific antibodies with a common heavy chain are disclosed in, e.g., US20120184716, US20130317200, and US20160264685A1, the contents of each of which is incorporated by reference herein.

[0383] Amino Acid Modifications

[0384] Alternative compositions and methods of producing multispecific antibodies with correct light chain pairing include various amino acid modifications. For example, Zymeworks describes heterodimers with one or more amino acid modifications in the CHI and / or CL domains, one or more amino acid modifications in the VH and / or VL domains, or any combination thereof, which are part of the interface between the light chain and heavy chain and create preferential pairing between each heavy chain and a desired light chain such that when the two heavy chains and two light chains of the heterodimer pair are co expressed in a cell, the heavy chain of the first heterodimer preferentially pairs with one of the light chains ratherthan the other (see e.g., W02015181805). Other exemplary methods are described in WO2016026943 (Argen-X), US20150211001, US20140072581A1, US20160039947A1, and US20150368352.

[0385] Lambda / Kappa Formats

[0386] Multispecific molecules (e.g., multispecific antibody molecules) that include the lambda light chain polypeptide and a kappa light chain polypeptides, can be used to allow for heterodimerization. Methods for generating bispecific antibody molecules comprising the lambda light chain polypeptide and a kappa light chain polypeptides are disclosed in PCT / US17 / 53053 filed on September 22, 2017, incorporated herein by reference in its entirety.

[0387] In some embodiments, the multispecific molecules includes a multispecific antibody molecule, e.g., an antibody molecule comprising two binding specificities, e.g., a bispecific antibody molecule. The multispecific antibody molecule includes:

[0388] a lambda light chain polypeptide 1 (LLCP1) specific for a first epitope;

[0389] a heavy chain polypeptide 1 (HCP1) specific for the first epitope;

[0390] a kappa light chain polypeptide 2 (KLCP2) specific for a second epitope; and

[0391] a heavy chain polypeptide 2 (HCP2) specific for the second epitope.

[0392] ‘ ‘Lambda light chain polypeptide 1 (LLCP1)”, as that term is used herein, refers to a polypeptide comprising sufficient light chain (LC) sequence, such that when combined with a cognate heavy chain variable region, can mediate specific binding to its epitope and complex with an HCP 1. In some embodiments, it comprises all or a fragment of a CHI region. In some embodiments, an LLCP1 comprises LC-CDR1, LC-CDR2, LC-CDR3, FR1, FR2, FR3, FR4, and CHI, or sufficient sequence therefrom to mediate specific binding of its epitope and complex with an HCP 1. LLCP 1 , together with its HCP 1 , provide specificity for a first epitope (while KLCP2, together with its HCP2, provide specificity for a second epitope). As described elsewhere herein, LLCP1 has a higher affinity for HCP1 than for HCP2.

[0393] “Kappa light chain polypeptide 2 (KLCP2)”, as that term is used herein, refers to a polypeptide comprising sufficient light chain (LC) sequence, such that when combined with a cognate heavy chain variable region, can mediate specific binding to its epitope and complex with an HCP2. In some embodiments, it comprises all or a fragment of a CHI region. In some embodiments, a KLCP2 comprises LC-CDR1, LC-CDR2, LC-CDR3, FR1, FR2, FR3, FR4, and CHI, or sufficient sequence therefrom to mediate specific binding of its epitope and complex with an HCP2. KLCP2, together with its HCP2, provide specificity for a second epitope (while LLCP1, together with its HCP1, provide specificity for a first epitope).

[0394] “Heavy chain polypeptide 1 (HCP1)”, as that term is used herein, refers to a polypeptide comprising sufficient heavy chain (HC) sequence, e.g., HC variable region sequence, such that when combined with a cognate LLCP1, can mediate specific binding to its epitope and complex with an HCP1. In some embodiments, it comprises all or a fragment of a CHI region. In some embodiments, it comprises all or a fragment of a CH2 and / or CH3 region. In some embodiments, an HCP1 comprises HC-CDR1, HC- CDR2, HC-CDR3, FR1, FR2, FR3, FR4, CHI, CH2, and CH3, or sufficient sequence therefrom to: (i) mediate specific binding of its epitope and complex with an LLCP1, (ii) to complex preferentially, as described herein to LLCP1 as opposed to KLCP2; and (iii) to complex preferentially, as described herein, to an HCP2, as opposed to another molecule of HCP 1. HCP1, together with its LLCP1, provide specificity for a first epitope (while KLCP2, together with its HCP2, provide specificity for a second epitope).

[0395] “Heavy chain polypeptide 2 (HCP2)”, as that term is used herein, refers to a polypeptide comprising sufficient heavy chain (HC) sequence, e.g., HC variable region sequence, such that when combined with a cognate LLCP1, can mediate specific binding to its epitope and complex with an HCP1. In some embodiments, it comprises all or a fragment of a CHI region. In some embodiments, it comprises all or a fragment of a CH2 and / or CH3 region. In some embodiments, an HCP1 comprises HC-CDR1, HC- CDR2, HC-CDR3, FR1, FR2, FR3, FR4, CHI, CH2, and CH3, or sufficient sequence therefrom to: (i) mediate specific binding of its epitope and complex with an KLCP2, (ii) to complex preferentially, asdescribed herein to KLCP2 as opposed to LLCP1; and (iii) to complex preferentially, as described herein, to an HCP1, as opposed to another molecule of HCP2. HCP2, together with its KLCP2, provide specificity for a second epitope (while LLCP1, together with its HCP1, provide specificity for a first epitope).

[0396] In some embodiments of the multispecific antibody molecule disclosed herein:

[0397] LLCP 1 has a higher affinity for HCP 1 than for HCP2; and / or

[0398] KLCP2 has a higher affinity for HCP2 than for HCP 1.

[0399] In some embodiments, the affinity of LLCP 1 for HCP1 is sufficiently greater than its affinity for HCP2, such that under preselected conditions, e.g., in aqueous buffer, e.g., at pH 7, in saline, e.g., at pH 7, or under physiological conditions, at least 75%, 80, 90, 95, 98, 99, 99.5, or 99.9 % of the multispecific antibody molecule molecules have a LLCP1 complexed, or interfaced with, a HCP1.

[0400] In some embodiments of the multispecific antibody molecule disclosed herein:

[0401] the HCP1 has a greater affinity for HCP2, than for a second molecule of HCP 1; and / or

[0402] the HCP2 has a greater affinity for HCP1, than for a second molecule of HCP2.

[0403] In some embodiments, the affinity of HCP 1 for HCP2 is sufficiently greater than its affinity for a second molecule of HCP 1, such that under preselected conditions, e.g., in aqueous buffer, e.g., at pH 7, in saline, e.g., at pH 7, or under physiological conditions, at least 75%, 80, 90, 95, 98, 99 99.5 or 99.9 % of the multispecific antibody molecule molecules have a HCP1 complexed, or interfaced with, a HCP2.

[0404] In another aspect, disclosed herein is a method for making, or producing, a multispecific antibody molecule, e.g., as a first or second tumor-targeting moiety of a multispecific or multifunctional molecule polypeptide of the invention. The method includes:

[0405] (i) providing a first heavy chain polypeptide (e.g., a heavy chain polypeptide comprising one, two, three or all of a first heavy chain variable region (first VH), a first CHI, a first heavy chain constant region (e.g., a first CH2, a first CH3, or both));

[0406] (ii) providing a second heavy chain polypeptide (e.g., a heavy chain polypeptide comprising one, two, three or all of a second heavy chain variable region (second VH), a second CHI, a second heavy chain constant region (e.g., a second CH2, a second CH3, or both));

[0407] (iii) providing a lambda chain polypeptide (e.g., a lambda light variable region (VLZ). a lambda light constant chain (VLZ). or both) that preferentially associates with the first heavy chain polypeptide (e.g., the first VH); and

[0408] (iv) providing a kappa chain polypeptide (e.g., a lambda light variable region (VLZ). a lambda light constant chain (VLZ). or both) that preferentially associates with the second heavy chain polypeptide (e.g., the second VH),

[0409] under conditions where (i)-(iv) associate.

[0410] In some embodiments, the first and second heavy chain polypeptides form an Fc interface that enhances heterodimerization.

[0411] In some embodiments, (i)-(iv) (e.g., nucleic acid encoding (i)-(iv)) are introduced in a single cell, e.g., a single mammalian cell, e.g., a CHO cell. In some embodiments, (i)-(iv) are expressed in the cell.

[0412] In some embodiments, (i)-(iv) (e.g., nucleic acid encoding (i)-(iv)) are introduced in different cells, e.g., different mammalian cells, e.g., two or more CHO cell. In some embodiments, (i)-(iv) are expressed in the cells.

[0413] In some embodiments, the method further comprises purifying a cell-expressed antibody molecule, e.g., using a lambda- and / or- kappa-specific purification, e.g., affinity chromatography.

[0414] In some embodiments, the method further comprises evaluating the cell-expressed multispecific antibody molecule. For example, the purified cell-expressed multispecific antibody molecule can be analyzed by techniques known in the art, include mass spectrometry. In some embodiments, the purified cell-expressed antibody molecule is cleaved, e.g., digested with papain to yield the Fab moieties and evaluated using mass spectrometry.

[0415] In some embodiments, the method produces correctly paired kappa / lambda multispecific, e.g., bispecific, antibody molecules in a high yield, e.g., at least 75, 80, 90, 95, 98, 99 99.5 or 99.9%.

[0416] In other embodiments, the multispecific, e.g., a bispecific, antibody molecule that includes:

[0417] (i) a first heavy chain polypeptide (HCP1) (e.g., a heavy chain polypeptide comprising one, two, three or all of a first heavy chain variable region (first VH), a first CHI, a first heavy chain constant region (e.g., a first CH2, a first CH3, or both)), e.g., wherein the HCP1 binds to a first epitope;

[0418] (ii) a second heavy chain polypeptide (HCP2) (e.g., a heavy chain polypeptide comprising one, two, three or all of a second heavy chain variable region (second VH), a second CHI, a second heavy chain constant region (e.g., a second CH2, a second CH3, or both)), e.g., wherein the HCP2 binds to a second epitope;

[0419] (iii) a lambda light chain polypeptide (LLCP1) (e.g., a lambda light variable region (VL1), a lambda light constant chain (VL1), or both) that preferentially associates with the first heavy chain polypeptide (e.g., the first VH), e.g., wherein the LLCP1 binds to a first epitope; and

[0420] (iv) a kappa light chain polypeptide (KLCP2) (e.g., a lambda light variable region (VLk), a lambda light constant chain (VLk), or both) that preferentially associates with the second heavy chain polypeptide (e.g., the second VH), e.g., wherein the KLCP2 binds to a second epitope.

[0421] In some embodiments, the first and second heavy chain polypeptides form an Fc interface that enhances heterodimerization. In some embodiments, the multispecific antibody molecule has a first binding specificity that includes a hybrid VL1-CL1 heterodimerized to a first heavy chain variable region connected to the Fc constant, CH2-CH3 domain (having a knob modification) and a second binding specificity that includes a hybrid VLk-CLk heterodimerized to a second heavy chain variable region connected to the Fc constant, CH2-CH3 domain (having a hole modification).

[0422] Other exemplary multispecific antibody formats include, e.g., those described in the following US20160114057A1, US20130243775A1, US20140051833, US20130022601, US20150017187A1, US20120201746A1, US20150133638A1, US20130266568A1, US20160145340A1, WO2015127158A1, US20150203591A1, US20140322221A1, US20130303396A1, US20110293613, US20130017200A1, US20160102135A1, WO2015197598A2, WO2015197582A1, US9359437, US20150018529,WO2016115274A1, WO2016087416A1, US20080069820A1, US9145588B, US7919257, and US20150232560A1. Exemplary multispecific molecules utilizing a full antibody-Fab / scFab format include those described in the following, US9382323B2, US20140072581A1, US20140308285A1, US20130165638A1, US20130267686A1, US20140377269A1, US7741446B2, and WO 1995009917A1. Exemplary multispecific molecules utilizing a domain exchange format include those described in the following, US20150315296A1, W02016087650A1, US20160075785A1, WO2016016299A1, US20160130347A1, US20150166670, US8703132B2, US20100316645, US8227577B2, US20130078249.Multifunctional Molecule Configurations

[0423] In some embodiments, the multifunctional molecule comprises the first polypeptide comprising the anti-G6B antibody or binding fragment thereof, and the second polypeptide comprising the anti-CD34 antibody or binding fragment thereof, wherein: (i) the first polypeptide comprises the anti-G6B antibody or binding fragment thereof linked to the first member of the dimerization module, and the second polypeptide comprises the anti-CD34 antibody or binding fragment thereof linked to the second member of the dimerization module; (ii) the first polypeptide comprises a first portion of the anti-G6B antibody or binding fragment thereof linked to the first member of the dimerization module, and the second polypeptide comprises a first portion of the anti-CD34 antibody or binding fragment thereof linked to the second member of the dimerization module; wherein the multifunctional molecule further comprises a third polypeptide comprising a second portion of the anti-G6B antibody or binding fragment thereof and a fourth polypeptide comprising a second portion of the anti-CD34 antibody or binding fragment thereof; (iii) the first polypeptide comprises a first portion of the anti-G6B antibody or binding fragment thereof linked to the first member of the dimerization module, and the second polypeptide comprises the anti-CD34 antibody or binding fragment thereof linked to the second member of the dimerization module; wherein the multifunctional molecule further comprises a third polypeptide comprising a second portion of the anti-G6B antibody or binding fragment thereof; or (iv) the first polypeptide comprises the anti-G6B antibody or binding fragment thereof linked to the first member of the dimerization module, and the second polypeptide comprises a first portion of the anti-CD34 antibody or binding fragment thereof linked to the second member of the dimerization module; wherein the multifunctional molecule further comprises a third polypeptide comprising a second portion of the anti-CD34 antibody or binding fragment thereof.

[0424] In some embodiments, the anti-G6B antibody or binding fragment thereof and the first member of the dimerization module, the anti-CD34 antibody or binding fragment thereof and the second member of the dimerization module, the first portion of the anti-G6B antibody or binding fragment thereof and the first member of the dimerization module, and the first portion of the anti-CD34 antibody or binding fragment thereof and the second member of the dimerization module are independently linked by a linker.

[0425] In some embodiments, the multifunctional molecule comprises the first polypeptide comprising the anti-G6B antibody or binding fragment thereof and the anti-CD34 antibody or binding fragment thereof, wherein the first polypeptide comprises: (i) the anti-G6B antibody or binding fragment thereof linked to thefirst member of the dimerization module linked to the anti-CD34 antibody or binding fragment thereof; (ii) a first portion of the anti-G6B antibody or binding fragment thereof linked to the first member of the dimerization module linked to a first portion of the anti-CD34 antibody or binding fragment thereof, wherein the multifunctional molecule further comprises a third polypeptide comprising a second portion of the anti- G6B antibody or binding fragment thereof and a fourth polypeptide comprising a second portion of the anti- CD34 antibody or binding fragment thereof; (iii) a first portion of the anti-G6B antibody or binding fragment thereof linked to the first member of the dimerization module linked to the anti-CD34 antibody or binding fragment thereof, wherein the multifunctional molecule further comprises a third polypeptide comprising a second portion of the anti-G6B antibody or binding fragment thereof; or (iv) the anti-G6B antibody or binding fragment thereof linked to the first member of the dimerization module linked to a first portion of the anti-CD34 antibody or binding fragment thereof, wherein the multifunctional molecule further comprises a third polypeptide comprising a second portion of the anti-CD34 antibody or binding fragment thereof.

[0426] In some embodiments, the anti-G6B antibody or binding fragment thereof and the first member of the dimerization module, the anti-CD34 antibody or binding fragment thereof and the first member of the dimerization module, the first portion of the anti-G6B antibody or binding fragment thereof and the first member of the dimerization module, and the first portion of the anti-CD34 antibody or binding fragment thereof and the first member of the dimerization module are independently linked by a linker. 00427] In some embodiments, the anti-G6B antibody or binding fragment thereof, the anti-CD34 antibody or binding fragment thereof, or any combination thereof is a full-length antibody, a Fab, a F(ab’)2, an Fv, a single chain Fv, a single domain antibody, a half arm antibody, a diabody (dAb), a bivalent antibody, a monovalent antibody, a bispecific antibody or fragment thereof, or a camelid antibody. In some embodiments, the anti-G6B antibody or binding fragment thereof and the anti-CD34 antibody or binding fragment thereof are independently the Fab or the scFv.

[0428] In some embodiments, the anti-G6B antibody or binding fragment thereof and the anti-CD34 antibody or binding fragment thereof are independently the scFv, and wherein the VH and VL of the anti- G6B antibody or binding fragment thereof, and the VH and VL of the anti-CD34 antibody or binding fragment thereof are independently linked by a linker.

[0429] In some embodiments, the first portion of the anti-G6B antibody or binding fragment thereof and the first portion of the anti-CD34 antibody or binding fragment thereof are independently the VH of the anti- G6B antibody or binding fragment thereof and the VH of the anti-CD34 antibody or binding fragment thereof, respectively, and the second portion of the anti-G6B antibody or binding fragment thereof and the second portion of the anti-CD34 antibody or binding fragment thereof are independently the VL of the anti- G6B antibody or binding fragment thereof and the VL of the anti-CD34 antibody or binding fragment thereof, respectively; or wherein the first portion of the anti-G6B antibody or binding fragment thereof and the first portion of the anti-CD34 antibody or binding fragment thereof are independently the VL of the anti- G6B antibody or binding fragment thereof and the VL of the anti-CD34 antibody or binding fragmentthereof, respectively, and the second portion of the anti-G6B antibody or binding fragment thereof and the second portion of the anti-CD34 antibody or binding fragment thereof are independently the VH of the anti- G6B antibody or binding fragment thereof and the VH of the anti-CD34 antibody or binding fragment thereof, respectively.

[0430] In some embodiments, the anti-G6B antibody or binding fragment thereof, the anti-CD34 antibody or binding fragment thereof, or any combination thereof is independently a murine, human, or humanized antibody or binding fragment thereof.

[0431] In some embodiments, the multifunctional molecule as provided herein comprises the following configuration:A-, B-[dimerization module] -C, -D

[0432] (e.g., the configuration shown in FIGs. 1A, IB, and 1C), wherein:

[0433] (1) the dimerization module comprises an immunoglobulin constant domain, e.g., a heavy chain constant domain (e.g., a homodimeric or heterodimeric heavy chain constant region, e.g., an Fc region), or a constant domain of an immunoglobulin variable region (e.g., a Fab region); and

[0434] (2) A, B, C, and D are independently: (a) absent; (b) the first tumor-targeting moiety; (c) the second tumor-targeting moiety; (d) the third tumor-targeting moiety; (e) the immune cell engager; (f) the cytokine molecule or the modulator of a cytokine molecule; or (g) the stromal modifying moiety.

[0435] In some embodiments, the multifunctional molecule as described herein comprises:

[0436] (i) A comprises the first tumor-targeting moiety, B comprises the second tumor-targeting moiety, C comprises a first immune cell engager, and D comprises a second immune cell engager (e.g., C and D comprise the same or different immune cell engagers);

[0437] (ii) A comprises the first tumor-targeting moiety, B comprises the second tumor-targeting moiety, C comprises a first cytokine molecule or modulator of a cytokine molecule, and D comprises a second cytokine molecule or modulator of a cytokine molecule (e.g., C and D comprise the same or different cytokine molecules, or C and D comprise the same or different modulators of a cytokine molecule);

[0438] (iii) A comprises the first tumor-targeting moiety, B comprises the second tumor-targeting moiety, C comprises a first stromal modifying moiety, and D comprises a second stromal modifying moiety (e.g., C and D comprise the same or different stromal modifying moieties);

[0439] (iv) A comprises the first tumor-targeting moiety, B comprises the second tumor-targeting moiety, C comprises the immune cell engager, and D comprises the cytokine molecule or the modulator of a cytokine molecule;

[0440] (v) A comprises the first tumor-targeting moiety, B comprises the second tumor-targeting moiety, C comprises the cytokine molecule or the modulator of a cytokine molecule, and D comprises the immune cell engager;

[0441] (vi) A comprises the first tumor-targeting moiety, B comprises the second tumor-targeting moiety, C comprises the immune cell engager, and D comprises the stromal modifying moiety;

[0442] (vii) A comprises the first tumor-targeting moiety, B comprises the second tumor-targetingmoiety, C comprises the stromal modifying moiety, and D comprises the immune cell engager;

[0443] (viii) A comprises the first tumor-targeting moiety, B comprises the second tumor-targeting moiety, C comprises the cytokine molecule or the modulator of a cytokine molecule, and D comprises the stromal modifying moiety;

[0444] (ix) A comprises the first tumor-targeting moiety, B comprises the second tumor-targeting moiety, C comprises the stromal modifying moiety, and D comprises the cytokine molecule or the modulator of a cytokine molecule;

[0445] (x) A comprises the first tumor-targeting moiety, B comprises the second tumor-targeting moiety, C comprises the immune cell engager, and D is absent;

[0446] (xi) A comprises the first tumor-targeting moiety, B comprises the second tumor-targeting moiety, C is absent, and D comprises the immune cell engager;

[0447] (xii) A comprises the first tumor-targeting moiety, B comprises the second tumor-targeting moiety, C comprises the cytokine molecule or the modulator of a cytokine molecule, and D is absent;

[0448] (xiii) A comprises the first tumor-targeting moiety, B comprises the second tumor-targeting moiety, C is absent, and D comprises the cytokine molecule or the modulator of a cytokine molecule;

[0449] (xiv) A comprises the first tumor-targeting moiety, B comprises the second tumor-targeting moiety, C comprises the stromal modifying moiety, and D is absent;

[0450] (xv) A comprises the first tumor-targeting moiety, B comprises the second tumor-targeting moiety, C is absent, and D comprises the stromal modifying moiety;

[0451] (xvi) A comprises the first tumor-targeting moiety, B comprises the second tumor-targeting moiety, C comprises the third tumor-targeting moiety, and D comprises the immune cell engager;

[0452] (xvii) A comprises the first tumor-targeting moiety, B comprises the second tumor-targeting moiety, C comprises the third tumor-targeting moiety, and D comprises the cytokine molecule or the modulator of a cytokine molecule; or

[0453] (xviii) A comprises the first tumor-targeting moiety, B comprises the second tumor-targeting moiety, C comprises the third tumor-targeting moiety, and D comprises a stromal modifying moiety.

[0454] In some embodiments, the dimerization module comprises a first immunoglobulin chain constant region and a second immunoglobulin chain constant region. In some embodiments, A and C are linked to the first immunoglobulin chain constant region; and B and D are linked to the second immunoglobulin chain constant region. In some embodiments, the first immunoglobulin chain constant region comprises the first fragment crystallizable region (Fc region) and the second first immunoglobulin chain constant region comprises the second fragment crystallizable region (Fc region). In some embodiments, dimerization of the first Fc region and the second Fc region is enhanced by providing an Fc interface of the first Fc region and the second Fc region with one or more of a paired cavity-protuberance, an electrostatic interaction, or a strand -exchange, such that a greater ratio of heteromultimer to homomultimer forms relative to a nonengineered interface.

[0455] In some embodiments, the multifunctional molecule further comprises any one selected from thegroup consisting of an immune cell engager, a cytokine molecule, a modulator of a cytokine molecule, a stromal modifying moiety, a tumor targeting moiety, and any combination thereof, wherein the immune cell engager is selected from the group consisting of a T cell engager, an NK cell engager, a B cell engager, a macrophage cell engager, and a dendritic cell engager.

[0456] In some embodiments, the immune cell engager, the cytokine molecule, the modulator of a cytokine molecule, the stromal modifying moiety, the tumor targeting moiety, or any combination thereof is linked to the first polypeptide, the second polypeptide, the third polypeptide, the fourth polypeptide, or any combination thereof.

[0457] In some embodiments, the immune cell engager, the cytokine molecule, the modulator of a cytokine molecule, the stromal modifying moiety, the tumor targeting moiety, or any combination thereof is within a single contiguous polypeptide chain of the first polypeptide, the second polypeptide, the third cytokine polypeptide, or the fourth cytokine polypeptide to which the immune cell engager, the cytokine molecule, the modulator of a cytokine molecule, the stromal modifying moiety, the tumor targeting moiety, or any combination thereof is linked.

[0458] In some embodiments, the immune cell engager, the cytokine molecule, the modulator of a cytokine molecule, the stromal modifying moiety, the tumor targeting moiety, or any combination thereof is linked to the first polypeptide, the second polypeptide, the third cytokine polypeptide, or the fourth cytokine polypeptide by a linker.

[0459] In some embodiments, disclosed herein are multifunctional molecules that include a plurality of (e.g., two or more) functionalities (or binding specificities), comprising (i) a first tumor-targeting moiety that binds to a first tumor antigen and (ii) a second tumor-targeting moiety that binds to a second tumor antigen, wherein the first and second tumor antigens are each independently selected from the group consisting of: CD34, G6B, and any combination thereof. In some embodiments, the multifunctional molecules are multispecific molecules. In some embodiments, the multifunctional molecule further comprises one, two, or all of: (iii) an immune cell engager selected from the group consisting of a T cell engager, an NK cell engager, a B cell engager, a dendritic cell engager, and a macrophage cell engager; (iv) a cytokine molecule; (v) a modulator of a cytokine molecule; (vi) a stromal modifying moiety; and (vii) a third tumor-targeting moiety that is selected from the group consisting of: CD41, P-selectin, Clec2, cKIT, FLT3, MPL, ITGB3, ITGB2, GP5, GP6, GP9, GP1BA, DSC2, FCGR2A, TNFRSF10A, TNFRSF10B, TM4SF1, and any combination thereof. In some embodiments, the third tumor antigen is different from the first tumor antigen or second tumor antigen. In some embodiments, the first tumor antigen, the second tumor antigen, and optionally the third tumor antigens are expressed on the same tumor cell.

[0460] In some embodiments, the multifunctional molecule is a bifunctional molecule, a trifunctional molecule, or a tetrafunctional molecule. In some embodiments, the multifunctional molecule is a bispecific molecule, a trispecific molecule, or a tetraspecific molecule.

[0461] Without being bound by theory, in some embodiments, the multifunctional molecules disclosed herein localizes and / or activate an immune cell in the presence of a cell expressing the first tumor antigen,the second tumor antigen, or any combination thereof. In some embodiments, the multifunctional molecules disclosed herein localizes and / or activate an immune cell in the presence of a cell expressing the first tumor antigen, the second tumor antigen, the third tumor antigen, or any combination thereof. In some embodiments, the multifunctional molecules disclosed herein bridges an immune cell and a target cell that expresses the first tumor antigen, the second tumor antigen, or any combination thereof. In some embodiments, the multifunctional molecules disclosed herein bridges an immune cell and a target cell that expresses the first tumor antigen, the second tumor antigen, the third tumor antigen, or any combination thereof. In some embodiments, the immune effector cell is selected from the group consisting of a T cell, an NK cell, a B cell, a dendritic cell, and a macrophage. In some embodiments, increasing the proximity and / or activity of the immune cell, in the presence of the target cell expressing the first tumor antigen, the second tumor antigen, or any combination thereof, using the multifunctional molecules described herein enhances an immune response against the target cell, thereby providing a more effective therapy. In some embodiments, increasing the proximity and / or activity of the immune cell, in the presence of the target cell expressing the first tumor antigen, the second tumor antigen, the third tumor antigen, or any combination thereof, using the multifunctional molecules described herein enhances an immune response against the target cell, thereby providing a more effective therapy.

[0462] In some embodiments, novel multifunctional molecules include (i) a stromal modifying moiety and (ii) a first tumor-targeting moiety that binds to a first tumor antigen, a second tumor-targeting moiety that binds to a second tumor antigen, and optionally a third tumor-targeting moiety that binds to a third tumor antigen. Without being bound by theory, in some embodiments, the multifunctional molecules disclosed herein inter alia target (e.g., localize to) a cancer site, and alter the tumor stroma, e.g., alter the tumor microenvironment near the cancer site. In some embodiments, the multifunctional molecules can further include one or both of: an immune cell engager (e.g., selected from one, two, three, or all of a T cell engager, NK cell engager, a B cell engager, a dendritic cell engager, and a macrophage cell engager); and / or a cytokine molecule or a modulator of a cytokine molecule. Accordingly, provided herein are, inter alia, multispecific or multifunctional molecules (e.g., multispecific or multifunctional antibody molecules) that include the aforesaid moieties, nucleic acids encoding the same, methods of producing the aforesaid molecules, and methods of treating a disease or disorder, e.g., cancer, using the aforesaid molecules.

[0463] In some embodiments, an antibody molecule is a multispecific or multifunctional antibody molecule, e.g., it comprises a plurality of immunoglobulin variable domains sequences, wherein a first immunoglobulin variable domain sequence of the plurality has binding specificity for a first epitope and a second immunoglobulin variable domain sequence of the plurality has binding specificity for a second epitope. In some embodiments, the first and second epitopes are on the same antigen, e.g., the same protein (or subunit of a multimeric protein). In some embodiments, the first and second epitopes overlap. In some embodiments, the first and second epitopes do not overlap. In some embodiments, the first and second epitopes are on different antigens, e.g., the different proteins (or different subunits of a multimeric protein). In some embodiments, a multispecific antibody molecule comprises a third, fourth or fifth immunoglobulinvariable domain. In some embodiments, a multispecific antibody molecule is a bispecific antibody molecule, a trispecific antibody molecule, or a tetraspecific antibody molecule.

[0464] In some embodiments, a multispecific antibody molecule is a bispecific antibody molecule. A bispecific antibody has specificity for no more than two antigens. A bispecific antibody molecule is characterized by a first immunoglobulin variable domain sequence which has binding specificity for a first epitope and a second immunoglobulin variable domain sequence that has binding specificity for a second epitope. In some embodiments, the first and second epitopes are on the same antigen, e.g., the same protein (or subunit of a multimeric protein). In some embodiments, the first and second epitopes overlap. In some embodiments, the first and second epitopes do not overlap. In some embodiments, the first and second epitopes are on different antigens, e.g., the different proteins (or different subunits of a multimeric protein). In some embodiments, a bispecific antibody molecule comprises a heavy chain variable domain sequence and a light chain variable domain sequence which have binding specificity for a first epitope and a heavy chain variable domain sequence and a light chain variable domain sequence which have binding specificity for a second epitope. In some embodiments, a bispecific antibody molecule comprises a half antibody having binding specificity for a first epitope and a half antibody having binding specificity for a second epitope. In some embodiments, a bispecific antibody molecule comprises a half antibody, or fragment thereof, having binding specificity for a first epitope and a half antibody, or fragment thereof, having binding specificity for a second epitope. In some embodiments, a bispecific antibody molecule comprises a scFv or a Fab, or fragment thereof, have binding specificity for a first epitope and a scFv or a Fab, or fragment thereof, have binding specificity for a second epitope.

[0465] In some embodiments, multispecific antibody molecules can comprise more than one antigenbinding site, where different sites are specific for different antigens. In some embodiments, multispecific antibody molecules can bind more than one (e.g., two or more) epitopes on the same antigen. In some embodiments, multispecific antibody molecules comprise an antigen-binding site specific for a target cell (e.g., cancer cell) and a different antigen-binding site specific for an immune effector cell. In some embodiments, the multispecific antibody molecule is a bispecific antibody molecule. Bispecific antibody molecules can be classified into five different structural groups: (i) bispecific immunoglobulin G (BsIgG); (ii) IgG appended with an additional antigen-binding moiety; (iii) bispecific antibody fragments; (iv) bispecific fusion proteins; and (v) bispecific antibody conjugates.

[0466] BsIgG is a format that is monovalent for each antigen. Exemplary BsIgG formats include but are not limited to crossMab, DAF (two-in-one), DAF (four-in-one), DutaMab, DT-IgG, knobs-in-holes common LC, knobs-in-holes assembly, charge pair, Fab-arm exchange, SEEDbody, triomab, LUZ-Y, Fcab, KA-body. orthogonal Fab. See Spiess et al. Mol. Immunol. 67(2015) : 95- 106. Exemplary BsIgGs include catumaxomab (Fresenius Biotech, Trion Pharma, Neopharm), which contains an anti-CD3 arm and an anti-EpCAM arm; and ertumaxomab (Neovii Biotech, Fresenius Biotech), which targets CD3 and HER2. In some embodiments, BsIgG comprises heavy chains that are engineered for heterodimerization. For example, heavy chains can be engineered for heterodimerization using a “knobs-into-holes” strategy, a SEEDplatform, a common heavy chain (e.g., in K -bodies), and use of heterodimeric Fc regions. See Spiess et al. Mol. Immunol. 67(2015):95-106. Strategies that have been used to avoid heavy chain pairing of homodimers in BsIgG include knobs-in-holes, duobody, azymetric, charge pair, HA-TF, SEEDbody, and differential protein A affinity. See Id. BsIgG can be produced by separate expression of the component antibodies in different host cells and subsequent purification / assembly into a BsIgG. BsIgG can also be produced by expression of the component antibodies in a single host cell. BsIgG can be purified using affinity chromatography, e.g., using protein A and sequential pH elution.

[0467] IgG appended with an additional antigen-binding moiety is another format of bispecific antibody molecules. For example, monospecific IgG can be engineered to have bispecificity by appending an additional antigen-binding unit onto the monospecific IgG, e.g., at the N- or C- terminus of either the heavy or light chain. Exemplary additional antigen-binding units include single domain antibodies (e.g., variable heavy chain or variable light chain), engineered protein scaffolds, and paired antibody variable domains (e.g., single chain variable fragments or variable fragments). See Id. Examples of appended IgG formats include dual variable domain IgG (DVD-Ig), IgG(H)-scFv, scFv-(H)IgG, IgG(L)-scFv, scFv-(L)IgG, IgG(L,H)-Fv, IgG(H)-V, V(H)-IgG, IgG(L)-V, V(L)-IgG, KIH IgG-scFab, 2scFv-IgG, IgG-2scFv, scFv4-Ig, zybody, and DVI-IgG (four-in-one). See Spiess et al. Mol. Immunol. 67(2015):95-106. An example of an IgG-scFv is MM-141 (Merrimack Pharmaceuticals), which binds IGF-1R and HER3. Examples of DVD-Ig include ABT-981 (AbbVie), which binds IL-la and IL- 1 (3; and ABT-122 (AbbVie), which binds TNF and IL-17A.

[0468] Bispecific antibody fragments (BsAb) are a format of bispecific antibody molecules that lack some or all of the antibody constant domains. For example, some BsAb lack an Fc region. In some embodiments, bispecific antibody fragments include heavy and light chain regions that are connected by a peptide linker that permits efficient expression of the BsAb in a single host cell. Exemplary bispecific antibody fragments include but are not limited to nanobody, nanobody-HAS, BiTE, Diabody, DART, TandAb, scDiabody, scDiabody-CH3, Diabody-CH3, triple body, miniantibody, minibody, TriBi minibody, scFv-CH3 KIH, Fab-scFv, scFv-CH-CL-scFv, F(ab’)2, F(ab’)2-scFv2, scFv-KIH, Fab-scFv-Fc, tetravalent HCAb, scDiabody-Fc, Diabody-Fc, tandem scFv-Fc, and intrabody. See Id. For example, the BiTE format comprises tandem scFvs, where the component scFvs bind to CD3 on T cells and a surface antigen on cancer cells.

[0469] Bispecific fusion proteins include antibody fragments linked to other proteins, e.g., to add additional specificity and / or functionality. An example of a bispecific fusion protein is an immTAC, which comprises an anti-CD3 scFv linked to an affinity-matured T-cell receptor that recognizes HLA-presented peptides. In some embodiments, the dock-and-lock (DNL) method can be used to generate bispecific antibody molecules with higher valency. Also, fusions to albumin binding proteins or human serum albumin can be extend the serum half-life of antibody fragments. See Id.

[0470] In some embodiments, chemical conjugation, e.g., chemical conjugation of antibodies and / or antibody fragments, can be used to create BsAb molecules. See Id. An exemplary bispecific antibodyconjugate includes the CovX-body format, in which a low molecular weight drug is conjugated site- specifically to a single reactive lysine in each Fab arm or an antibody or fragment thereof. In some embodiments, the conjugation improves the serum half-life of the low molecular weight drug. An exemplary CovX-body is CVX-241 (NCTO 1004822), which comprises an antibody conjugated to two short peptides inhibiting either VEGF or Ang2. See Id.

[0471] The antibody molecules can be produced by recombinant expression, e.g., of at least one or more component, in a host system. Exemplary host systems include eukaryotic cells (e.g., mammalian cells, e.g., CHO cells, or insect cells, e.g., SF9 or S2 cells) and prokaryotic cells (e.g., E. coli). Bispecific antibody molecules can be produced by separate expression of the components in different host cells and subsequent purification / assembly. Alternatively, the antibody molecules can be produced by expression of the components in a single host cell. Purification of bispecific antibody molecules can be performed by various methods such as affinity chromatography, e.g., using protein A and sequential pH elution. In other embodiments, affinity tags can be used for purification, e.g., histidine-containing tag, myc tag, or streptavidin tag.

[0472] In some embodiments, the multifunctional molecule further comprises one of the immune cell engager, the cytokine molecule or the modulator of a cytokine molecule, and the stromal modifying moiety.

[0473] In some embodiments, the multifunctional molecule further comprises: the immune cell engager, and / or the tumor-targeting moiety, the cytokine molecule or the modulator of a cytokine molecule, and / or the tumor-targeting moiety, or the stromal modifying moiety, and / or the tumor-targeting moiety.

[0474] In some embodiments, the multifunctional molecule further comprises two of the immune cell engager, the cytokine molecule or the modulator of a cytokine molecule, and the stromal modifying moiety.

[0475] In some embodiments, the multifunctional molecule further comprises: the immune cell engager, the cytokine molecule or the modulator of a cytokine molecule, and / or the tumor-targeting moiety, the immune cell engager, the stromal modifying moiety, and / or the tumor-targeting moiety, or the cytokine molecule or the modulator of a cytokine molecule, the stromal modifying moiety, and / or the tumor-targeting moiety.

[0476] In some embodiments, the multifunctional molecule further comprises all of the immune cell engager, the cytokine molecule or the modulator of a cytokine molecule, and the stromal modifying moiety.

[0477] In some embodiments, the multifunctional molecule further comprises: the immune cell engager, the cytokine molecule or the modulator of a cytokine molecule, the stromal modifying moiety, and / or the tumor-targeting moiety.

[0478] In some embodiments, the multifunctional molecule further comprises an immune cell engager selected from the group consisting of a T cell engager, an NK cell engager, a B cell engager, a dendritic cell engager, and a macrophage cell engager.

[0479] In some embodiments, the multifunctional molecule further comprises the immune cell engager that binds to and activates an immune cell, e.g., an effector cell.

[0480] In some embodiments, the multifunctional molecule further comprises the immune cell engagerthat binds to, but does not activate, an immune cell, e.g., an effector cell.

[0481] In some embodiments, the multifunctional molecule further comprises the immune cell engager that is a T cell engager, e.g., a T cell engager that mediates binding to and activation of a T cell, or a T cell engager that mediates binding to but not activation of a T cell.

[0482] In some embodiments, the multifunctional molecule further comprises the immune cell engager that is an NK cell engager, e.g., an NK cell engager that mediates binding to and activation of an NK cell, or an NK cell engager that mediates binding to but not activation of an NK cell. In some embodiments, the multifunctional molecule further comprises the NK cell engager that is an antibody molecule, e.g., an antigen binding domain. In some embodiments, the multifunctional molecule further comprises the NK cell engager that is an antibody molecule, e.g., an antigen binding domain, that binds to NKp30 or NKp46. In some embodiments, the multifunctional molecule further comprises the NK cell engager that is a ligand, optionally, the ligand further comprises an immunoglobulin constant region, e.g., an Fc region. In some embodiments, the multifunctional molecule further comprises the NK cell engager that is a ligand of NKp44 or NKp46, e.g., a viral HA. In some embodiments, the multifunctional molecule further comprises the NK cell engager that is a ligand of DAP 10, e.g., a coreceptor for NKG2D. In some embodiments, the multifunctional molecule further comprises the NK cell engager that is a ligand of CD16, e.g., a CD16a / b ligand, e.g., a CD16a / b ligand further comprising an antibody Fc region.

[0483] In some embodiments, the multifunctional molecule further comprises the immune cell engager that mediates binding to, or activation of, or both of, one or more of a B cell, a macrophage, and / or a dendritic cell.

[0484] In some embodiments, the multifunctional molecule as provided herein comprises the form of an antibody-drug conjugate. In some embodiments, the multifunctional molecule as provided herein comprises a biologically active payload or drug linked to an anti-G6B antibody as provided herein, an anti-CD34 antibody as provided herein, or a combination thereof.

[0485] In some embodiments, the biologically active payload or drug comprises a cytotoxic agent, an anticancer agent, or a combination thereof. In some embodiments, the biologically active payload or drug comprises a chemotherapeutic agent as described herein, a biologic as described herein, a cancer therapeutic antibody as described herein, a viral cancer therapeutic agent as described herein, a nanopharmaceutical as described herein, paclitaxel or a paclitaxel formulation as described herein, a cancer therapeutic agent as described herein, a tyrosine kinase inhibitor as described herein, an anti-angiogenic agent as described herein, a vascular targeting agent as described herein, a vascular disrupting agent as described herein, or any combination thereof. In some embodiments, the biologically active payload or drug comprises a cytotoxin, a chemotherapeutic agent, or a combination thereof. In some embodiments, the biologically active payload or drug comprises a microtubulin inhibitor, a DNA binder, a topoisomerase inhibitor, a glucocorticoid receptor modulator, an oligonucleotide molecule, or any combination thereof. In some embodiments, exemplary microtubulin inhibitors include, but are not limited to, monomethyl auristatin A (MMAE), monomethyl auristatin F (MMAF), and mertansine. In some embodiments, exemplary DNA binders include, but are notlimited to, calicheamicin. In some embodiments, exemplary topoisomerase inhibitors include, but are not limited to, a topoisomerase 1 inhibitor, such as SN-38 and exatecan. In some embodiments, exemplary glucocorticoid receptor modulators include, but are not limited to, dexamethasone and budesonide. In some embodiments, the oligonucleotide molecule comprises an inhibitory oligonucleotide molecule. In some embodiments, the inhibitory oligonucleotide molecules include, but are not limited to, an siRNA, an shRNA, an RNAi agent, a miRNA, an antisense oligonucleotide molecule, or any combination thereof. As used herein, the term “RNAi agent” refers to an agent that induces or promotes RNA interference. As used herein, the term “shRNA”, also known as “short hairpin RNA” or “small hairpin RNA,” refers to an artificial RNA molecule with a tight hairpin turn that can be used to silence target gene expression and / or activity via RNA interference. As used herein, the term “siRNA”, also known as “small interfering RNA,” “short interfering RNA”, or “silencing RNA,” refers to a class of double-stranded RNA at first non-coding RNA molecules, typically 20-24 (normally 21) base pairs in length, and operating within the RNA interference pathway. As used herein, the term “miRNA,” “microRNA,” or “miR” refers to a small, single-stranded, non-coding RNA molecules containing 21 to 23 nucleotides, which are involved in RNA silencing and post-transcriptional regulation of gene expression. As used herein, the term “antisense oligonucleotide molecule” refers to a single strand of DNA or RNA that is complementary to a chosen sequence, which prevents protein translation of certain messenger RNA strands by binding to them.

[0486] In some embodiments, the multifunctional molecule as provided herein comprises a linker that linked, connect, or conjugate the biologically active payload or drug to an anti-G6B antibody as provided herein, an anti-CD34 antibody as provided herein, or a combination thereof. In some embodiments, the linker comprises a chemical motif including disulfides, hydrazones, peptides, or thioethers. In some embodiments, the linker is cleavable. In some embodiments, the linker is non-cleavable. In some embodiments, the linker is an enzyme-sensitive cleavable linker. In some embodiments, the linker is cleavable by cathepsin.Tumor-targeting moieties

[0487] In some embodiments, the multifunctional molecule further comprises an antibody molecule that binds to a cancer antigen, e.g., a tumor antigen or a stromal antigen. In some embodiments, the cancer antigen is, e.g., a mammalian, e.g., a human, cancer antigen. In other embodiments, the antibody molecule binds to an immune cell antigen, e.g., a mammalian, e.g., a human, immune cell antigen. For example, the antibody molecule binds specifically to an epitope, e.g., linear or conformational epitope, on the cancer antigen or the immune cell antigen.

[0488] In some embodiments, the multifunctional molecule further comprises a tumor targeting moiety. In some embodiments, the tumor targeting moiety binds to any one selected from CD41, P-selectin, Clec2, cKIT, FLT3, MPL, ITGB3, ITGB2, GP5, GP6, GP9, GP1BA, DSC2, FCGR2A, TNFRSF10A, TNFRSF10B, or TM4SF1, alphafetoprotein (AFP), carcinoembryonic antigen (CEA), CA-125, MUC-1, epithelial tumor antigen (ETA), tyrosinase, melanoma-associated antigen (MAGE), HER2, B-cellmaturation antigen (BCMA), mesothelin, CD 19, or any combination thereof.

[0489] The present disclosure provides, inter alia, multispecific (e.g., bi-, tri-, tetra- specific) or multifunctional molecules, that include, e.g., are engineered to contain, one or more tumor-targeting moieties that bind to a tumor antigen, e.g., a tumor antigen selected from: CD41, P-selectin, Clec2, cKIT, FLT3, MPL, ITGB3, ITGB2, GP5, GP6, GP9, GP1BA, DSC2, FCGR2A, TNFRSF10A, TNFRSF10B, and TM4SF1.

[0490] CD41 refers to ITGA2B, also known as Integrin alpha-IIb. Swiss-Prot accession number P08514 provides exemplary human CD41 amino acid sequences. In some embodiments, CD41 or CD41 molecule is a naturally-existing CD41 or a functional variant or fragment thereof.

[0491] P-selectin refers to SELP, also known as CD62P, GMP-140 or LECAM3. Swiss-Prot accession number P16109 provides exemplary human P-selectin amino acid sequences. In some embodiments, P- selectin or P-selectin molecule is a naturally-existing P-selectin or a functional variant or fragme...

Claims

CLAIMSWHAT IS CLAIMED IS:

1. A composition comprising an anti-G6B antibody or binding fragment thereof, or a nucleic acid encoding the anti-G6B antibody or binding fragment thereof, wherein the anti-G6B antibody or binding fragment thereof comprises a heavy chain variable domain (VH) comprising a heavy chain complementarity determining region 3 (HC CDR3) of any one of the sequences selected from the group consisting of SEQ ID NOs: 204, 208, 211, 215, 219, 223, and 227.

2. The composition of claim 1, wherein the VH of the anti-G6B antibody or binding fragment thereof further comprises a heavy chain complementarity determining region 1 (HC CDR1) of any one of the sequences selected from the group consisting of SEQ ID NOs: 202, 206, 213, 217, 221, and 225.

3. The composition of any one of claims 1-2, wherein the VH of the anti-G6B antibody or binding fragment thereof further comprises a heavy chain complementarity determining region 2 (HC CDR2) of any one of the sequences selected from the group consisting of SEQ ID NOs: 203, 207, 210, 214, 218, 222, and 226.

4. The composition of any one of claims 1-3, wherein the anti-G6B antibody or binding fragment thereof comprises a light chain variable domain (VL) comprising a light chain complementarity determining region 3 (LC CDR3) of any one of the sequences selected from the group consisting of SEQ ID NOs: 231, 235, 239, 243, 247, 250, 254, 258, 262, 266, 270, 274, and 278.

5. The composition of any one of claims 1-4, wherein the VL of the anti-G6B antibody or binding fragment thereof further comprises a light chain complementarity determining region 1 (LC CDR1) of any one of the sequences selected from the group consisting of SEQ ID NOs: 229, 233, 237, 241, 245, 252, 256, 260, 264, 268, 272, and 276.

6. The composition of any one of claims 1-5, wherein the VL of the anti-G6B antibody or binding fragment thereof further comprises a light chain complementarity determining region 2 (LC CDR2) of any one of the sequences selected from the group consisting of SEQ ID NOs: 230, 234, 238, 242, 246, 249, 253, 257, 261, 265, 269, 273, and 277.

7. The composition of any one of claims 1-6, wherein the anti-G6B antibody or binding fragment thereof comprises:(i) the VH comprising the HC CDR1 of any one of the sequences selected from the group consisting of SEQ ID NOs: 202, 206, 213, 217, 221, and 225, the HC CDR2 of any one of the sequences selected from the group consisting of SEQ ID NOs: 203, 207, 210, 214, 218, 222, and 226, and the HC CDR3 of any one of the sequences selected from the group consisting of SEQ ID NOs: 204, 208, 211, 215, 219, 223, and 227;(ii) the VL comprising the LC CDR1 of any one of the sequences selected from the group consisting of SEQ ID NOs: 229, 233, 237, 241, 245, 252, 256, 260, 264, 268, 272, and 276, the LC CDR2 of any one of the sequences selected from the group consisting of SEQ ID NOs: 230, 234, 238, 242, 246, 249, 253, 257,261, 265, 269, 273, and 277, and the LC CDR3 of any one of the sequences selected from the group consisting of SEQ ID NOs: 231, 235, 239, 243, 247, 250, 254, 258, 262, 266, 270, 274, and 278; or(iii) any combination thereof.

8. The composition of any one of claims 1-7, wherein the anti-G6B antibody or binding fragment thereof comprises:(i) the VH comprising a HC CDR1, a HC CDR2 and a HC CDR3 of SEQ ID NOs: 202, 203, and 204, respectively; SEQ ID NOs: 206, 207, and 208, respectively; SEQ ID NOs: 206, 210, and 211, respectively; SEQ ID NOs: 213, 214, and 215, respectively; SEQ ID NOs: 217, 218, and 219, respectively; SEQ ID NOs: 221, 222, and 223, respectively; or SEQ ID NOs: 225, 226, and 227, respectively;(ii) the VL comprising a LC CDR1, a LC CDR2 and a LC CDR3 of SEQ ID NOs: 229, 230, and 231, respectively; SEQ ID NOs: 233, 234, and 235, respectively; SEQ ID NOs: 237, 238, and 239, respectively; SEQ ID NOs: 241, 242, and 243, respectively; SEQ ID NOs: 245, 246, and 247, respectively; SEQ ID NOs: 245, 249, and 250, respectively; SEQ ID NOs: 252, 253, and 254, respectively; SEQ ID NOs: 256, 257, and 258, respectively; SEQ ID NOs: 260, 261, and 262, respectively; SEQ ID NOs: 264, 265, and 266, respectively; SEQ ID NOs: 268, 269, and 270, respectively; SEQ ID NOs: 272, 273, and 274, respectively; or SEQ ID NOs: 276, 277, and 278, respectively; or(iii) any combination thereof.

9. The composition of any one of claims 1-8, wherein the anti-G6B antibody or binding fragment thereof comprises:(i) a VH comprising an amino acid sequence with at least 70% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 201, 205, 209, 212, 216, 220, and 224;(ii) a VL comprising an amino acid sequence with at least 70% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 228, 232, 236, 240, 244, 248, 251, 255, 259, 263, 267, 271, and 275; or(iii) any combination thereof.

10. The composition of any one of claims 1-8, wherein the anti-G6B antibody or binding fragment thereof comprises:(i) a VH comprising a sequence selected from the group consisting of SEQ ID NOs: 201, 205, 209, 212, 216, 220, and 224;(ii) a VL comprising a sequence selected from the group consisting of SEQ ID NOs: 228, 232, 236, 240, 244, 248, 251, 255, 259, 263, 267, 271, and 275; or(iii) any combination thereof.

11. The composition of any one of claims 1-8, wherein the anti-G6B antibody or binding fragment thereof comprises:(i) a VH of any one of the sequences of SEQ ID NOs: 201, 205, 209, 212, 216, 220, and 224;(ii) a VL of any one of the sequences of SEQ ID NOs: 228, 232, 236, 240, 244, 248, 251, 255, 259, 263, 267, 271, and 275; or(iii) any combination thereof.

12. The composition of any one of claims 1-11, wherein the anti-G6B antibody or binding fragment thereof comprises: a VH of SEQ ID NO: 201 and a VL of SEQ ID NO: 228; a VH of SEQ ID NO: 201 and a VL of SEQ ID NO: 232; a VH of SEQ ID NO: 201 and a VL of SEQ ID NO: 236; a VH of SEQ ID NO: 201 and a VL of SEQ ID NO: 240; a VH of SEQ ID NO: 201 and a VL of SEQ ID NO: 244; a VH of SEQ ID NO: 201 and a VL of SEQ ID NO: 248; a VH of SEQ ID NO: 201 and a VL of SEQ ID NO: 251; a VH of SEQ ID NO: 201 and a VL of SEQ ID NO: 255; a VH of SEQ ID NO: 201 and a VL of SEQ ID NO: 259; a VH of SEQ ID NO: 201 and a VL of SEQ ID NO: 263; a VH of SEQ ID NO: 201 and a VL of SEQ ID NO: 267; a VH of SEQ ID NO: 201 and a VL of SEQ ID NO: 271; a VH of SEQ ID NO: 201 and a VL of SEQ ID NO: 275; a VH of SEQ ID NO: 205 and a VL of SEQ ID NO: 228; a VH of SEQ ID NO: 205 and a VL of SEQ ID NO: 232; a VH of SEQ ID NO: 205 and a VL of SEQ ID NO: 236; a VH of SEQ ID NO: 205 and a VL of SEQ ID NO: 240; a VH of SEQ ID NO: 205 and a VL of SEQ ID NO: 244; a VH of SEQ ID NO: 205 and a VL of SEQ ID NO: 248; a VH of SEQ ID NO: 205 and a VL of SEQ ID NO: 251; a VH of SEQ ID NO: 205 and a VL of SEQ ID NO: 255; a VH of SEQ ID NO: 205 and a VL of SEQ ID NO: 259; a VH of SEQ ID NO: 205 and a VL of SEQ ID NO: 263; a VH of SEQ ID NO: 205 and a VL of SEQ ID NO: 267; a VH of SEQ ID NO: 205 and a VL of SEQ ID NO: 271; a VH of SEQ ID NO: 205 and a VL of SEQ ID NO: 275; a VH of SEQ ID NO: 209 and a VL of SEQ ID NO: 228; a VH of SEQ ID NO: 209 and a VL of SEQ ID NO: 232; a VH of SEQ ID NO: 209 and a VL of SEQ ID NO: 236; a VH of SEQ ID NO: 209 and a VL of SEQ ID NO: 240; a VH of SEQ ID NO: 209 and a VL of SEQ ID NO: 244; a VH of SEQ ID NO: 209 and a VL of SEQ ID NO: 248;aVHofSEQ ID NO: 209 andaVL ofSEQ ID NO: 251; a VH of SEQ ID NO: 209 and a VL of SEQ ID NO: 255; a VH of SEQ ID NO: 209 and a VL of SEQ ID NO: 259; a VH of SEQ ID NO: 209 and a VL of SEQ ID NO: 263; a VH of SEQ ID NO: 209 and a VL of SEQ ID NO: 267; aVHofSEQ ID NO: 209 andaVL ofSEQ ID NO: 271; a VH of SEQ ID NO: 209 and a VL of SEQ ID NO: 275; aVHofSEQ ID NO: 212 andaVL ofSEQ ID NO: 228; aVHofSEQ ID NO: 212 andaVL ofSEQ ID NO: 232; aVHofSEQ ID NO: 212 andaVL ofSEQ ID NO: 236; aVHofSEQ ID NO: 212 andaVL ofSEQ ID NO: 240; aVHofSEQ ID NO: 212 andaVL ofSEQ ID NO: 244; aVHofSEQ ID NO: 212 andaVL ofSEQ ID NO: 248; aVHofSEQ ID NO: 212 andaVL ofSEQ ID NO: 251; aVHofSEQ ID NO: 212 andaVL ofSEQ ID NO: 255; aVHofSEQ ID NO: 212 andaVL ofSEQ ID NO: 259; aVHofSEQ ID NO: 212 andaVL ofSEQ ID NO: 263; aVHofSEQ ID NO: 212 andaVL ofSEQ ID NO: 267; aVHofSEQ ID NO: 212 andaVL ofSEQ ID NO: 271; aVHofSEQ ID NO: 212 andaVL ofSEQ ID NO: 275; aVHofSEQ ID NO: 216 andaVL ofSEQ ID NO: 228; aVHofSEQ ID NO: 216 andaVL ofSEQ ID NO: 232; aVHofSEQ ID NO: 216 andaVL ofSEQ ID NO: 236; aVHofSEQ ID NO: 216 andaVL ofSEQ ID NO: 240; aVHofSEQ ID NO: 216 andaVL ofSEQ ID NO: 244; aVHofSEQ ID NO: 216 andaVL ofSEQ ID NO: 248; aVHofSEQ ID NO: 216andaVL ofSEQ ID NO: 251; aVHofSEQ ID NO: 216 andaVL ofSEQ ID NO: 255; aVHofSEQ ID NO: 216 andaVL ofSEQ ID NO: 259; aVHofSEQ ID NO: 216 andaVL ofSEQ ID NO: 263; aVHofSEQ ID NO: 216 andaVL ofSEQ ID NO: 267; aVHofSEQ ID NO: 216 andaVL ofSEQ ID NO: 271; aVHofSEQ ID NO: 216 andaVL ofSEQ ID NO: 275; a VH of SEQ ID NO: 220 and a VL of SEQ ID NO: 228; a VH of SEQ ID NO: 220 and a VL of SEQ ID NO: 232; a VH of SEQ ID NO: 220 and a VL of SEQ ID NO: 236; a VH of SEQ ID NO: 220 and a VL of SEQ ID NO: 240;a VH of SEQ ID NO: 220 and a VL of SEQ ID NO: 244; a VH of SEQ ID NO: 220 and a VL of SEQ ID NO: 248; a VH of SEQ ID NO: 220 and a VL of SEQ ID NO: 251; a VH of SEQ ID NO: 220 and a VL of SEQ ID NO: 255; a VH of SEQ ID NO: 220 and a VL of SEQ ID NO: 259; a VH of SEQ ID NO: 220 and a VL of SEQ ID NO: 263; a VH of SEQ ID NO: 220 and a VL of SEQ ID NO: 267; a VH of SEQ ID NO: 220 and a VL of SEQ ID NO: 271; a VH of SEQ ID NO: 220 and a VL of SEQ ID NO: 275; a VH of SEQ ID NO: 224 and a VL of SEQ ID NO: 228; a VH of SEQ ID NO: 224 and a VL of SEQ ID NO: 232; a VH of SEQ ID NO: 224 and a VL of SEQ ID NO: 236; a VH of SEQ ID NO: 224 and a VL of SEQ ID NO: 240; a VH of SEQ ID NO: 224 and a VL of SEQ ID NO: 244; a VH of SEQ ID NO: 224 and a VL of SEQ ID NO: 248; a VH of SEQ ID NO: 224 and a VL of SEQ ID NO: 251; a VH of SEQ ID NO: 224 and a VL of SEQ ID NO: 255; a VH of SEQ ID NO: 224 and a VL of SEQ ID NO: 259; a VH of SEQ ID NO: 224 and a VL of SEQ ID NO: 263; a VH of SEQ ID NO: 224 and a VL of SEQ ID NO: 267; a VH of SEQ ID NO: 224 and a VL of SEQ ID NO: 271; or a VH of SEQ ID NO : 224 and a VL of SEQ ID NO : 275.

13. The composition of any one of claims 1-12, wherein the anti-G6B antibody or binding fragment thereof is a full-length antibody, a Fab, a F(ab')2, an Fv, a single chain Fv (scFv), a single domain antibody, a half arm antibody, a diabody (dAb), a bivalent antibody, a monovalent antibody, a bispecific antibody or fragment thereof, or a camelid antibody.

14. The composition of claim 13, wherein the anti-G6B antibody or binding fragment thereof is the scFv, wherein the scFv comprises a VH and a VL operatively linked by a linker.

15. The composition of claim 14, wherein the linker is selected from the group consisting of a cleavable linker, a non-cleavable linker, a peptide linker, a flexible linker, a rigid linker, a helical linker, and a nonhelical linker.

16. The composition of claim 15, wherein the linker is the peptide linker, and wherein the linker comprises any one of the sequences selected from the group consisting of SEQ ID NOs: 69-72 and 295.

17. The composition of any one of claims 1-16, wherein the anti-G6B antibody or binding fragment thereof is a murine, human, or humanized antibody or binding fragment thereof.

18. The composition of any one of claims 1-17, wherein the composition further comprises an antigen binding moiety, an immune cell engager, a cytokine molecule, a modulator of a cytokine molecule, a stromal modifying moiety7, or any combination thereof, and wherein the immune cell engager is selected from the group consisting of a T cell engager, an NK cell engager, a B cell engager, a dendritic cell engager, and a macrophage cell engager.

19. The composition of claim 18, wherein the anti-G6B antibody or binding fragment thereof is linked to the antigen binding moiety, the immune cell engager, the cytokine molecule, the modulator of a cytokine molecule, the stromal modifying moiety, or any combination thereof.

20. The composition of claim 19, wherein the anti-G6B antibody or binding fragment thereof is linked to the antigen binding moiety, the immune cell engager, the cytokine molecule, the modulator of a cytokine molecule, the stromal modifying moiety, or any combination thereof by a linker.21 . The composition of any one of claims 18-20, wherein the antigen binding moiety is a tumor targeting moiety.

22. The composition of any one of claims 18-21, wherein the antigen binding moiety is an anti-CD34 antibody or binding fragment thereof.

23. A composition comprising an anti-CD34 antibody or binding fragment thereof, or a nucleic acid encoding the anti-CD34 antibody or binding fragment thereof, wherein the anti-CD34 antibody or binding fragment thereof comprises a heavy chain variable domain (VH) comprising a heavy chain complementarity determining region 3 (HC CDR3) of SEQ ID NO: 282.

24. The composition of claim 23, wherein the VH of the anti-CD34 antibody or binding fragment thereof further comprises a heavy chain complementarity determining region 1 (HC CDR1) of SEQ ID NO: 281.

25. The composition of any one of claims 23-24, wherein the VH of the anti-CD34 antibody or binding fragment thereof further comprises a heavy chain complementarity determining region 2 (HC CDR2) of SEQ ID NO: 280.

26. The composition of any one of claims 23-25, wherein the anti-CD34 antibody or binding fragment thereof comprises a light chain variable domain (VL) comprising a light chain complementarity determining region 3 (LC CDR3) of SEQ ID NO: 291.

27. The composition of any one of claims 23-26, wherein the VL of the anti-CD34 antibody or binding fragment thereof further comprises a light chain complementarity determining region 1 (LC CDR1) of SEQ ID NO: 290.

28. The composition of any one of claims 23-27, wherein the VL of the anti-CD34 antibody or binding fragment thereof further comprises a light chain complementarity determining region 2 (LC CDR2) of SEQ ID NO: 289.

29. The composition of any one of claims 23-28, wherein the anti-CD34 antibody or binding fragment thereof comprises:(i) the VH comprising the HC CDR1 of SEQ ID NO: 280, the HC CDR2 of SEQ ID NO: 281, and the HC CDR3 of SEQ ID NO: 282;(ii) the VL comprising the LC CDR1 of SEQ ID NO: 289, the LC CDR2 of SEQ ID NO: 290, and the LC CDR3 of SEQ ID NO: 291; or(iii) any combination thereof.

30. The composition of any one of claims 23-29, wherein the anti-CD34 antibody or binding fragment thereof comprises:(i) a VH comprising an amino acid sequence with at least 70% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 279, 283, 284, 285, 286, and 287;(ii) a VL comprising an amino acid sequence with at least 70% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 288, 292, 293, and 294; or(iii) any combination thereof.

31. The composition of any one of claims 23-29, wherein the anti-CD34 antibody or binding fragment thereof comprises:(i) a VH comprising a sequence selected from the group consisting of SEQ ID NOs: 279, 283, 284, 285, 286, and 287;(ii) a VL comprising a sequence selected from the group consisting of SEQ ID NOs: 292, 293, and 294; or(iii) any combination thereof.

32. The composition of any one of claims 23-29, wherein the anti-CD34 antibody or binding fragment thereof comprises:(i) a VH of any one of the sequence of SEQ ID NOs: 279, 283, 284, 285, 286, and 287;(ii) a VL of any one of the sequence of SEQ ID NOs: 292, 293, and 294; or(iii) any combination thereof.

33. The composition of any one of claims 23-32, wherein the anti-CD34 antibody or binding fragment thereof comprises: a VH of SEQ ID NO: 279 and a VL of SEQ ID NO: 292; a VH of SEQ ID NO: 279 and a VL of SEQ ID NO: 293; a VH of SEQ ID NO: 279 and a VL of SEQ ID NO: 294; a VH of SEQ ID NO: 283 and a VL of SEQ ID NO: 292; a VH of SEQ ID NO: 283 and a VL of SEQ ID NO: 293;a VH of SEQ ID NO: 283 and a VL of SEQ ID NO: 294; a VH of SEQ ID NO: 284 and a VL of SEQ ID NO: 292; a VH of SEQ ID NO: 284 and a VL of SEQ ID NO: 293; a VH of SEQ ID NO: 284 and a VL of SEQ ID NO: 294; a VH of SEQ ID NO: 285 and a VL of SEQ ID NO: 292; a VH of SEQ ID NO: 285 and a VL of SEQ ID NO: 293; a VH of SEQ ID NO: 285 and a VL of SEQ ID NO: 294; a VH of SEQ ID NO: 286 and a VL of SEQ ID NO: 292; a VH of SEQ ID NO: 286 and a VL of SEQ ID NO: 293; a VH of SEQ ID NO: 286 and a VL of SEQ ID NO: 294; a VH of SEQ ID NO: 287 and a VL of SEQ ID NO: 292; a VH of SEQ ID NO: 287 and a VL of SEQ ID NO: 293; or a VH of SEQ ID NO: 287 and a VL of SEQ ID NO: 294.

34. The composition of any one of claims 23-33, wherein the anti-CD34 antibody or binding fragment thereof is a full-length antibody, a Fab, a F(ab')2, an Fv, a single chain Fv, a single domain antibody, a half arm antibody, a diabody (dAb), a bivalent antibody, a monovalent antibody, a bispecific antibody or fragment thereof, or a camelid antibody.

35. The composition of claim 34, wherein the anti-CD34 antibody or binding fragment thereof is the scFv, wherein the scFv comprises a VH and a VL operatively linked by a linker.

36. The composition of claim 35, wherein the linker is selected from the group consisting of a cleavable linker, a non-cleavable linker, a peptide linker, a flexible linker, a rigid linker, a helical linker, and a nonhelical linker.

37. The composition of claim 36, wherein the linker is the peptide linker, and wherein the linker comprises any one of the sequences selected from the group consisting of SEQ ID NOs: 69-72 and 295.

38. The composition of any one of claims 23-37, wherein the anti-CD34 antibody or binding fragment thereof is a murine, human, or hum anized antibody or binding fragment thereof.

39. The composition of any one of claims 23-38, wherein the composition further comprises an antigen binding moiety, an immune cell engager, a cytokine molecule, a modulator of a cytokine molecule, a stromal modifying moiety, or any combination thereof, and wherein the immune cell engager is selected from the group consisting of a T cell engager, an NK cell engager, a B cell engager, a dendritic cell engager, and a macrophage cell engager.

40. The composition of claim 39, wherein the anti-CD34 antibody or binding fragment thereof is linked to the antigen binding moiety, the immune cell engager, the cytokine molecule, the modulator of a cytokine molecule, the stromal modifying moiety, or any combination thereof.41 . The composition of claim 40, wherein the anti-CD34 antibody or binding fragment thereof is linked to the antigen binding moiety, the immune cell engager, the cytokine molecule, the modulator of a cytokine molecule, the stromal modifying moiety, or any combination thereof by a linker.

42. The composition of any one of claims 39-41, wherein the antigen binding moiety is a tumor targeting moiety.

43. The composition of any one of claims 39-42, wherein the antigen binding moiety is an anti-G6B antibody or binding fragment thereof.

44. A composition comprising a multifunctional molecule or a nucleic acid encoding the multifunctional molecule, wherein the multifunctional molecule comprises an anti-G6B antibody or binding fragment thereof linked to an antigen binding moiety, wherein the anti-G6B antibody or binding fragment thereof compri ses a heavy chain variable domain (VH) comprising a heavy chain complementarity determining region 3 (HC CDR3) of any one of the sequences selected from the group consisting of SEQ ID NOs: 204, 208, 211, 215, 219, 223, and 227.

45. The composition of claim 44, wherein the antigen binding moiety is an anti-CD34 antibody or binding fragment thereof.

46. The composition of claim 45, wherein the anti-CD34 antibody or binding fragment thereof comprises a heavy chain variable domain (VH) comprising a heavy chain complementarity determining region 3 (HC CDR3) of SEQ ID NO: 282.

47. A composition comprising a multifunctional molecule or a nucleic acid encoding the multifunctional molecule, wherein the multifunctional molecule comprises an anti-CD34 antibody or binding fragment thereof linked to an antigen binding moiety, wherein the anti-CD34 antibody or binding fragment thereof comprises a heavy chain variable domain (VH) comprising a heavy chain complementarity determining region 3 (HC CDR3) of SEQ ID NO: 282.

48. The composition of claim 47, wherein the antigen binding moiety is an anti-G6B antibody or binding fragment thereof.

49. The composition of claim 48, wherein the anti-G6B antibody or binding fragment thereof comprises a heavy chain variable domain (VH) comprising a heavy chain complementarity determining region 3 (HC CDR3) of any one of the sequences selected from the group consisting of SEQ ID NOs: 204, 208, 211, 215, 219, 223, and 227.

50. The composition of any one of claims 44-49, wherein the VH of the anti-G6B antibody or binding fragment thereof further comprises a heavy chain complementarity determining region 1 (HC CDR1) of any one of the sequences selected from the group consisting of SEQ ID NOs: 202, 206, 213, 217, 221, and 225.

51. The composition of any one of claims 44-50, wherein the VH of the anti-G6B antibody or binding fragment thereof further comprises a heavy chain complementarity determining region 2 (HC CDR2) of any one of the sequences selected from the group consisting of SEQ ID NOs: 203, 207, 210, 214, 218, 222, and 226.

52. The composition of any one of claims 44-51, wherein the anti-G6B antibody or binding fragment thereof comprises a light chain variable domain (VL) comprising a light chain complementarity determining region 3 (LC CDR3) of any one of the sequences selected from the group consisting of SEQ ID NOs: 231, 235, 239, 243, 247, 250, 254, 258, 262, 266, 270, 274, and 278.

53. The composition of any one of claims 44-52, wherein the VL of the anti-G6B antibody or binding fragment thereof further comprises a light chain complementarity determining region 1 (LC CDR1) of any one of the sequences selected from the group consisting of SEQ ID NOs: 229, 233, 237, 241, 245, 252, 256,260, 264, 268, 272, and 276.

54. The composition of any one of claims 44-53, wherein the VL of the anti-G6B antibody or binding fragment thereof further comprises a light chain complementarity determining region 2 (LC CDR2) of any one of the sequences selected from the group consisting of SEQ ID NOs: 230, 234, 238, 242, 246, 249, 253, 257, 261, 265, 269, 273, and 277.

55. The composition of any one of claims 44-54, wherein the anti-G6B antibody or binding fragment thereof comprises:(i) the VH comprising the HC CDR1 of any one of the sequences selected from the group consisting of SEQ ID NOs: 202, 206, 213, 217, 221, and 225, the HC CDR2 of any one of the sequences selected from the group consisting of SEQ ID NOs: 203, 207, 210, 214, 218, 222, and 226, and the HC CDR3 of any one of the sequences selected from the group consisting of SEQ ID NOs: 204, 208, 211, 215, 219, 223, and 227;(ii) the VL comprising the LC CDR1 of any one of the sequences selected from the group consisting of SEQ ID NOs: 229, 233, 237, 241, 245, 252, 256, 260, 264, 268, 272, and 276, the LC CDR2 of any one of the sequences selected from the group consisting of SEQ ID NOs: 230, 234, 238, 242, 246, 249, 253, 257,261, 265, 269, 273, and 277, and the LC CDR3 of any one of the sequences selected from the group consisting of SEQ ID NOs: 231, 235, 239, 243, 247, 250, 254, 258, 262, 266, 270, 274, and 278; or(iii) any combination thereof.

56. The composition of any one of claims 44-55, wherein the anti-G6B antibody or binding fragment thereof comprises:(i) the VH comprising a HC CDR1, a HC CDR2 and a HC CDR3 of SEQ ID NOs: 202, 203, and 204, respectively; SEQ ID NOs: 206, 207, and 208, respectively; SEQ ID NOs: 206, 210, and 211, respectively; SEQ ID NOs: 213, 214, and 215, respectively; SEQ ID NOs: 217, 218, and 219, respectively; SEQ ID NOs: 221, 222, and 223, respectively; or SEQ ID NOs: 225, 226, and 227, respectively;(ii) the VL comprising a LC CDR1, a LC CDR2 and a LC CDR3 of SEQ ID NOs: 229, 230, and 231, respectively; SEQ ID NOs: 233, 234, and 235, respectively; SEQ ID NOs: 237, 238, and 239,respectively; SEQ ID NOs: 241, 242, and 243, respectively; SEQ ID NOs: 245, 246, and 247, respectively;SEQ ID NOs: 245, 249, and 250, respectively; SEQ ID NOs: 252, 253, and 254, respectively; SEQ ID NOs: 256, 257, and 258, respectively; SEQ ID NOs: 260, 261, and 262, respectively; SEQ ID NOs: 264, 265, and 266, respectively; SEQ ID NOs: 268, 269, and 270, respectively; SEQ ID NOs: 272, 273, and 274, respectively; or SEQ ID NOs: 276, 277, and 278, respectively; or(iii) any combination thereof.

57. The composition of any one of claims 44-56, wherein the anti-G6B antibody or binding fragment thereof comprises:(i) a VH comprising an amino acid sequence with at least 70% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 201, 205, 209, 212, 216, 220, and 224;(ii) a VL comprising an amino acid sequence with at least 70% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 228, 232, 236, 240, 244, 248, 251, 255, 259, 263, 267, 271, and 275; or(iii) any combination thereof.

58. The composition of any one of claims 44-56, wherein the anti-G6B antibody or binding fragment thereof comprises:(i) a VH comprising a sequence selected from the group consisting of SEQ ID NOs: 201, 205, 209, 212, 216, 220, and 224;(ii) a VL comprising a sequence selected from the group consisting of SEQ ID NOs: 228, 232, 236, 240, 244, 248, 251, 255, 259, 263, 267, 271, and 275; or(iii) any combination thereof.

59. The composition of any one of claims 44-56, wherein the anti-G6B antibody or binding fragment thereof comprises:(i) a VH of any one of the sequences of SEQ ID NOs: 201, 205, 209, 212, 216, 220, and 224;(ii) a VL of any one of the sequences of SEQ ID NOs: 228, 232, 236, 240, 244, 248, 251, 255, 259, 263, 267, 271, and 275; or(iii) any combination thereof.

60. The composition of any one of claims 44-59, wherein the anti-G6B antibody or binding fragment thereof comprises: a VH of SEQ ID NO: 201 and a VL of SEQ ID NO: 228; a VH of SEQ ID NO: 201 and a VL of SEQ ID NO: 232; a VH of SEQ ID NO: 201 and a VL of SEQ ID NO: 236; a VH of SEQ ID NO: 201 and a VL of SEQ ID NO: 240; a VH of SEQ ID NO: 201 and a VL of SEQ ID NO: 244; a VH of SEQ ID NO: 201 and a VL of SEQ ID NO: 248; a VH of SEQ ID NO: 201 and a VL of SEQ ID NO: 251;aVHofSEQ ID NO: 201 andaVL ofSEQ ID NO: 255; aVHofSEQ ID NO: 201 andaVL ofSEQ ID NO: 259; aVHofSEQ ID NO: 201 andaVL ofSEQ ID NO: 263; aVHofSEQ ID NO: 201 andaVL ofSEQ ID NO: 267; aVHofSEQ ID NO: 201 andaVL ofSEQ ID NO: 271; aVHofSEQ ID NO: 201 andaVL ofSEQ ID NO: 275; a VH of SEQ ID NO: 205 and a VL of SEQ ID NO: 228; a VH of SEQ ID NO: 205 and a VL of SEQ ID NO: 232; a VH of SEQ ID NO: 205 and a VL of SEQ ID NO: 236; a VH of SEQ ID NO: 205 and a VL of SEQ ID NO: 240; a VH of SEQ ID NO: 205 and a VL of SEQ ID NO: 244; a VH of SEQ ID NO: 205 and a VL of SEQ ID NO: 248; aVHofSEQ ID NO: 205 andaVL ofSEQ ID NO: 251; a VH of SEQ ID NO: 205 and a VL of SEQ ID NO: 255; a VH of SEQ ID NO: 205 and a VL of SEQ ID NO: 259; a VH of SEQ ID NO: 205 and a VL of SEQ ID NO: 263; a VH of SEQ ID NO: 205 and a VL of SEQ ID NO: 267; aVHofSEQ ID NO: 205 andaVL ofSEQ ID NO: 271; a VH of SEQ ID NO: 205 and a VL of SEQ ID NO: 275; a VH of SEQ ID NO: 209 and a VL of SEQ ID NO: 228; a VH of SEQ ID NO: 209 and a VL of SEQ ID NO: 232; a VH of SEQ ID NO: 209 and a VL of SEQ ID NO: 236; a VH of SEQ ID NO: 209 and a VL of SEQ ID NO: 240; a VH of SEQ ID NO: 209 and a VL of SEQ ID NO: 244; a VH of SEQ ID NO: 209 and a VL of SEQ ID NO: 248; aVHofSEQ ID NO: 209 andaVL ofSEQ ID NO: 251; a VH of SEQ ID NO: 209 and a VL of SEQ ID NO: 255; a VH of SEQ ID NO: 209 and a VL of SEQ ID NO: 259; a VH of SEQ ID NO: 209 and a VL of SEQ ID NO: 263; a VH of SEQ ID NO: 209 and a VL of SEQ ID NO: 267; aVHofSEQ ID NO: 209 andaVL ofSEQ ID NO: 271; a VH of SEQ ID NO: 209 and a VL of SEQ ID NO: 275; aVHofSEQ ID NO: 212 andaVL ofSEQ ID NO: 228; aVHofSEQ ID NO: 212 andaVL ofSEQ ID NO: 232; aVHofSEQ ID NO: 212 andaVL ofSEQ ID NO: 236; aVHofSEQ ID NO: 212 andaVL ofSEQ ID NO: 240; aVHofSEQ ID NO: 212 andaVL ofSEQ ID NO: 244;aVHofSEQ ID NO: 212 and a VL ofSEQ ID NO: 248; aVHofSEQ ID NO: 212 and a VL ofSEQ ID NO: 251; aVHofSEQ ID NO: 212 and a VL ofSEQ ID NO: 255; aVHofSEQ ID NO: 212 and a VL ofSEQ ID NO: 259; aVHofSEQ ID NO: 212 and a VL ofSEQ ID NO: 263; aVHofSEQ ID NO: 212 and a VL ofSEQ ID NO: 267; aVHofSEQ ID NO: 212 and a VL ofSEQ ID NO: 271; aVHofSEQ ID NO: 212 and a VL ofSEQ ID NO: 275; aVHofSEQ ID NO: 216 and a VL ofSEQ ID NO: 228; aVHofSEQ ID NO: 216 and a VL ofSEQ ID NO: 232; aVHofSEQ ID NO: 216 and a VL ofSEQ ID NO: 236; aVHofSEQ ID NO: 216 and a VL ofSEQ ID NO: 240; aVHofSEQ ID NO: 216 and a VL ofSEQ ID NO: 244; aVHofSEQ ID NO: 216 and a VL ofSEQ ID NO: 248; aVHofSEQ ID NO: 216andaVL ofSEQ ID NO: 251; aVHofSEQ ID NO: 216 and a VL ofSEQ ID NO: 255; aVHofSEQ ID NO: 216 and a VL ofSEQ ID NO: 259; aVHofSEQ ID NO: 216 and a VL ofSEQ ID NO: 263; aVHofSEQ ID NO: 216 and a VL ofSEQ ID NO: 267; aVHofSEQ ID NO: 216 and a VL ofSEQ ID NO: 271; aVHofSEQ ID NO: 216 and a VL ofSEQ ID NO: 275; a VH of SEQ ID NO: 220 and a VL of SEQ ID NO: 228; a VH of SEQ ID NO: 220 and a VL of SEQ ID NO: 232; a VH of SEQ ID NO: 220 and a VL of SEQ ID NO: 236; a VH of SEQ ID NO: 220 and a VL of SEQ ID NO: 240; a VH of SEQ ID NO: 220 and a VL of SEQ ID NO: 244; a VH of SEQ ID NO: 220 and a VL of SEQ ID NO: 248; aVHofSEQ ID NO: 220 andaVL ofSEQ ID NO: 251; a VH of SEQ ID NO: 220 and a VL of SEQ ID NO: 255; a VH of SEQ ID NO: 220 and a VL of SEQ ID NO: 259; a VH of SEQ ID NO: 220 and a VL of SEQ ID NO: 263; a VH of SEQ ID NO: 220 and a VL of SEQ ID NO: 267; aVHofSEQ ID NO: 220 andaVL ofSEQ ID NO: 271; a VH of SEQ ID NO: 220 and a VL of SEQ ID NO: 275; a VH of SEQ ID NO: 224 and a VL of SEQ ID NO: 228; a VH of SEQ ID NO: 224 and a VL of SEQ ID NO: 232; a VH of SEQ ID NO: 224 and a VL of SEQ ID NO: 236;a VH of SEQ ID NO: 224 and a VL of SEQ ID NO: 240; a VH of SEQ ID NO: 224 and a VL of SEQ ID NO: 244; a VH of SEQ ID NO: 224 and a VL of SEQ ID NO: 248; a VH of SEQ ID NO: 224 and a VL of SEQ ID NO: 251; a VH of SEQ ID NO: 224 and a VL of SEQ ID NO: 255; a VH of SEQ ID NO: 224 and a VL of SEQ ID NO: 259; a VH of SEQ ID NO: 224 and a VL of SEQ ID NO: 263; a VH of SEQ ID NO: 224 and a VL of SEQ ID NO: 267; a VH of SEQ ID NO: 224 and a VL of SEQ ID NO: 271; or a VH of SEQ ID NO : 224 and a VL of SEQ ID NO : 275.

61. The composition of any one of claims 44-60, wherein the VH of the anti-CD34 antibody or binding fragment thereof further comprises a heavy chain complementarity determining region 1 (HC CDR1) of SEQ ID NO: 281.

62. The composition of any one of claims 44-61, wherein the VH of the anti-CD34 antibody or binding fragment thereof further comprises a heavy chain complementarity determining region 2 (HC CDR2) of SEQ ID NO: 280.

63. The composition of any one of claims 44-62, wherein the anti-CD34 antibody or binding fragment thereof comprises a light chain variable domain (VL) comprising a light chain complementarity determining region 3 (LC CDR3) of SEQ ID NO: 291.

64. The composition of any one of claims 44-63, wherein the VL of the anti-CD34 antibody or binding fragment thereof further comprises a light chain complementarity determining region 1 (LC CDR1) of SEQ ID NO: 290.

65. The composition of any one of claims 44-64, wherein the VL of the anti-CD34 antibody or binding fragment thereof further comprises a light chain complementarity determining region 2 (LC CDR2) of SEQ ID NO: 289.

66. The composition of any one of claims 44-65, wherein the anti-CD34 antibody or binding fragment thereof comprises:(i) the VH comprising the HC CDR1 of SEQ ID NO: 280, the HC CDR2 of SEQ ID NO: 281, and the HC CDR3 of SEQ ID NO: 282;(ii) the VL comprising the LC CDR1 of SEQ ID NO: 289, the LC CDR2 of SEQ ID NO: 290, and the LC CDR3 of SEQ ID NO: 291; or(iii) any combination thereof.

67. The composition of any one of claims 44-66, wherein the anti-CD34 antibody or binding fragment thereof comprises:(i) a VH comprising an amino acid sequence with at least 70% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 279, 283, 284, 285, 286, and 287;(ii) a VL comprising an amino acid sequence with at least 70% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 288, 292, 293, and 294; or(iii) any combination thereof.

68. The composition of any one of claims 44-66, wherein the anti-CD34 antibody or binding fragment thereof comprises:(i) a VH comprising a sequence selected from the group consisting of SEQ ID NOs: 279, 283, 284, 285, 286, and 287;(ii) a VL comprising a sequence selected from the group consisting of SEQ ID NOs: 288, 292, 293, and 294; or(iii) any combination thereof.

69. The composition of any one of claims 44-66, wherein the anti-CD34 antibody or binding fragment thereof comprises:(i) a VH of any one of the sequence of SEQ ID NOs: 279, 283, 284, 285, 286, and 287;(ii) a VL of any one of the sequence of SEQ ID NOs: 288, 292, 293, and 294; or(iii) any combination thereof.

70. The composition of any one of claims 44-69, wherein the anti-CD34 antibody or binding fragment thereof comprises: a VH of SEQ ID NO: 279 and a VL of SEQ ID NO: 292; a VH of SEQ ID NO: 279 and a VL of SEQ ID NO: 293; a VH of SEQ ID NO: 279 and a VL of SEQ ID NO: 294; a VH of SEQ ID NO: 283 and a VL of SEQ ID NO: 292; a VH of SEQ ID NO: 283 and a VL of SEQ ID NO: 293; a VH of SEQ ID NO: 283 and a VL of SEQ ID NO: 294; a VH of SEQ ID NO: 284 and a VL of SEQ ID NO: 292; a VH of SEQ ID NO: 284 and a VL of SEQ ID NO: 293; a VH of SEQ ID NO: 284 and a VL of SEQ ID NO: 294; a VH of SEQ ID NO: 285 and a VL of SEQ ID NO: 292; a VH of SEQ ID NO: 285 and a VL of SEQ ID NO: 293; a VH of SEQ ID NO: 285 and a VL of SEQ ID NO: 294; a VH of SEQ ID NO: 286 and a VL of SEQ ID NO: 292; a VH of SEQ ID NO: 286 and a VL of SEQ ID NO: 293; a VH of SEQ ID NO: 286 and a VL of SEQ ID NO: 294; a VH of SEQ ID NO: 287 and a VL of SEQ ID NO: 292; a VH of SEQ ID NO: 287 and a VL of SEQ ID NO: 293; ora VH of SEQ ID NO: 287 and a VL of SEQ ID NO: 294.71 . The composition of any one of claims 44-70, wherein the multifunctional molecule further comprises:(i) a constant heavy chain 1 domain (CHI) linked to the VH of anti-G6B antibody or binding fragment thereof, a CHI linked to the VH of the anti-CD34 antibody or binding fragment thereof, or any combination thereof;(ii) a consttint light chain domain (CL) linked to the VL of the anti-G6B antibody or binding fragment thereof, a CL linked to the VL of the anti-CD34 antibody or binding fragment thereof, or any combination thereof; or(iii) any combination thereof.

72. The composition of claim 71, wherein the CHI linked to the VH of anti-G6B antibody or binding fragment thereof and the CHI linked to the VH of the anti-CD34 antibody or binding fragment thereof are independently a CHI of IgGI, IgG2, IgG3, IgGAl, IgGA2, IgG4, IgJ, IgM, IgD, or IgE.

73. Hie composition of claim 71, wherein the CHI linked to the VH of anti-G6B antibody or binding fragment thereof and the CHI linked to the VH of the anti-CD34 antibody or binding fragment thereof independently comprise any one of the CHI sequences selected from the group consisting of SEQ ID NOs: 299, 300, and 302-309.

74. Tire composition of any one of claims 71-73, wherein the CL linked to the VL of the anti-G6B antibody or binding fragment thereof and the CL linked to the VL of the anti-CD34 antibody or binding fragment thereof are independently a CL of a lambda light chain or a CL of a kappa light chain.

75. The composition of any one of claims 71-73, wherein the CL linked to the VL of the anti-G6B antibody or binding fragment thereof and the CL linked to the VL of the anti-CD34 antibody or binding fragment thereof independently comprise any one of the sequences selected from the group consisting of SEQ ID NOs: 297 and 298.

76. The composition of any one of claims 44-75, wherein the anti-G6B antibody or binding fragment thereof and the anti-CD34 antibody or binding fragment thereof is covalently linked or non-covalently linked.

77. The composition of any one of claims 44-76, wherein the multifunctional molecule comprises a first polypeptide comprising(i) the anti-G6B antibody or binding fragment thereof linked to the anti-CD34 antibody or binding fragment thereof;(ii) a first portion of the anti-G6B antibody or binding fragment thereof linked to a first portion of the anti-CD34 antibody or binding fragment thereof, wherein the multifunctional molecule further comprises a second polypeptide comprising a second portion of the anti-G6B antibody or binding fragment thereof and a third polypeptide comprising a second portion of the anti-CD34 antibody or binding fragment thereof;(iii) a first portion of the anti-G6B antibody or binding fragment thereof linked to the anti-CD34 antibody or binding fragment thereof, wherein the multifunctional molecule further comprises a second polypeptide comprising a second portion of the anti-G6B antibody or binding fragment thereof; or(iv) the anti-G6B antibody or binding fragment thereof linked to a first portion of the anti-CD34 antibody or binding fragment thereof, wherein the multifunctional molecule further comprises a second polypeptide comprising a second portion of the anti-CD34 antibody or binding fragment thereof.

78. The composition of claim 77, wherein the anti-G6B antibody or binding fragment thereof and the anti-CD34 antibody or binding fragment thereof, the first portion of the anti-G6B antibody or binding fragment thereof and the first portion of the anti-CD34 antibody or binding fragment thereof, the first portion of the anti-G6B antibody or binding fragment thereof and the anti-CD34 antibody or binding fragment thereof, or the anti-G6B antibody or binding fragment thereof and the first portion of the anti- CD34 antibody or binding fragment thereof are independently linked by a linker.

79. The composition of any one of claims 44-76, wherein the multifunctional molecule comprises at least two non-contiguous polypeptide chains.

80. The composition of claim 79, wherein a first polypeptide comprises a first member of a dimerization module and a second polypeptide comprises a second member of the dimerization module, wherein the first polypeptide and the second polypeptide form a complex via the first member of the dimerization module and the second member of the dimerization module.

81. The composition of claim 80, wherein the first member of the dimerization module is a firs t Fc region, and the second member of the dimerization module is a second Fc region.

82. The composition of claim 81, wherein the first Fc region and the second Fc region are independently an IgGl Fc region or fragment thereof, an IgG2 Fc region or fragment thereof, an IgG3 Fc region or fragment thereof, an IgGA 1 Fc region or fragment thereof, an IgGA2 Fc region or fragment thereof, an IgG4 Fc region or fragment thereof, an IgJ Fc region or fragment thereof, an IgM Fc region or fragment thereof, an IgD Fc region or fragment thereof, or an IgE Fc region or fragment thereof.

83. "lire composition of claim 82, wherein the first Fc region and tire second Fc region independently comprise any one of the Fc sequences selected from the group consisting of SEQ ID NOs: 302-307.

84. The composition of any one of claims 81-83, wherein the first Fc region is an engineered first Fc region comprising a knob and the second Fc region is an engineered second Fc region comprising a hole, or wherein the first Fc region is an engineered first Fc region comprising a hole and the second Fc region is an engineered second Fc region comprising a knob.

85. The composition of claim 84, wherein the engineered first Fc region comprises the sequence of SEQ ID NO: 310 or SEQ ID NO: 312 and the engineered second Fc region comprises tire sequence of SEQ ID NO: 311 or SEQ ID NO: 313, or wherein the engineered first Fc region comprises the sequence of SEQ IDNO: 311 or SEQ ID NO: 313 and the engineered second Fc region comprises the sequence of SEQ ID NO:310 or SEQ ID NO: 31286. The composition of any one of claims 79-85, wherein the multifunctional molecule comprises the first polypeptide comprising the anti-G6B antibody or binding fragment thereof, and the second polypeptide comprising the anti-CD34 antibody or binding fragment thereof, wherein:(i) the first polypeptide comprises the anti-G6B antibody or binding fragment thereof linked to the first member of the dimerization module, and the second polypeptide comprises the anti-CD34 antibody or binding fragment thereof linked to the second member of the dimerization module;(ii) the first polypeptide comprises a first portion of the anti-G6B antibody or binding fragment thereof linked to the first member of the dimerization module, and the second polypeptide comprises a first portion of the anti-CD34 antibody or binding fragment thereof linked to the second member of the dimerization module; wherein the multifunctional molecule further comprises a third polypeptide comprising a second portion of the anti-G6B antibody or binding fragment thereof and a fourth polypeptide comprising a second portion of the anti-CD34 antibody or binding fragment thereof;(iii) the first polypeptide comprises a first portion of the anti-G6B antibody or binding fragment thereof linked to the first member of the dimerization module, and the second polypeptide comprises the anti-CD34 antibody or binding fragment thereof linked to the second member of the dimerization module; wherein the multifunctional molecule further comprises a third polypeptide comprising a second portion of the anti-G6B antibody or binding fragment thereof; or(iv) the first polypeptide comprises the anti-G6B antibody or binding fragment thereof linked to the first member of the dimerization module, and the second polypeptide comprises a first portion of the anti- CD34 antibody or binding fragment thereof linked to the second member of the dimerization module; wherein the multifunctional molecule further comprises a third polypeptide comprising a second portion of the anti-CD34 antibody or binding fragment thereof.

87. The composition of claim 86, wherein the anti-G6B antibody or binding fragment thereof and the first member of the dimerization module, the anti-CD34 antibody or binding fragment thereof and the second member of the dimerization module, the first portion of the anti-G6B antibody or binding fragment thereof and the first member of the dimerization module, and the first portion of the anti-CD34 antibody or binding fragment thereof and the second member of the dimerization module are independently linked by a linker.

88. The composition of any one of claims 79-85, wherein the multifunctional molecule comprises the first polypeptide comprising the anti-G6B antibody or binding fragment thereof and the anti-CD34 antibody or binding fragment thereof, wherein the first polypeptide comprises:(i) the anti-G6B antibody or binding fragment thereof linked to the first member of the dimerization module linked to the anti-CD34 antibody or binding fragment thereof;(ii) a first portion of the anti-G6B antibody or binding fragment thereof linked to the first member of the dimerization module linked to a first portion of the anti-CD34 antibody or binding fragment thereof, wherein the multifunctional molecule further comprises a third polypeptide comprising a second portion of the anti-G6B antibody or binding fragment thereof and a fourth polypeptide comprising a second portion of the anti-CD34 antibody or binding fragment thereof;(iii) a first portion of the anti-G6B antibody or binding fragment thereof linked to the first member of the dimerization module linked to the anti-CD34 antibody or binding fragment thereof, wherein the multifunctional molecule further comprises a third polypeptide comprising a second portion of the anti-G6B antibody or binding fragment thereof; or(iv) the anti-G6B antibody or binding fragment thereof linked to the first member of the dimerization module linked to a first portion of the anti-CD34 antibody or binding fragment thereof, wherein the multifunctional molecule further comprises a third polypeptide comprising a second portion of the anti- CD34 antibody or binding fragment thereof.

89. The composition of claim 88, wherein the anti-G6B antibody or binding fragment thereof and the first member of the dimerization module, the anti-CD34 antibody or binding fragment thereof and the first member of the dimerization module, the first portion of the anti-G6B antibody or binding fragment thereof and the first member of the dimerization module, and the first portion of the anti-CD34 antibody or binding fragment thereof and the first member of the dim eri zation module are independently linked by a linker.

90. The composition of any one of claims 44-89, wherein the anti-G6B antibody or binding fragment thereof, the anti-CD34 antibody or binding fragment thereof, or any combination thereof is a full-length antibody, a Fab, a F(ab')2, an Fv, a single chain Fv, a single domain antibody, a half arm antibody, a diabody (dAb), a bivalent antibody, a monovalent antibody, a bispecific antibody or fragment thereof, or a camelid antibody.91 . The composition of claim 90, wherein the anti-G6B antibody or binding fragment thereof and the anti-CD34 antibody or binding fragment thereof are independently the Fab or the scFv.

92. Tire composition of claim 91, wherein the anti-G6B antibody or binding fragment thereof and the anti-CD34 antibody or binding fragment thereof are independently the scFv, and wherein the VH and VL of the anti-G6B antibody or binding fragment thereof, and the VH and VL of the anti-CD34 antibody or binding fragment thereof are independently linked by a linker.

93. The composition of any one of claims 44-92, wherein the first portion of the anti-G6B antibody or binding fragment thereof and the first portion of the anti-CD34 antibody or binding fragment thereof are independently the VH of the anti-G6B antibody or binding fragment thereof and the VH of the anti-CD34 antibody or binding fragment thereof, respectively, and the second portion of the anti-G6B antibody or binding fragment thereof and the second portion of the anti-CD34 antibody or binding fragment thereof are independently the VL of the anti-G6B antibody or binding fragment thereof and the VL of the anti-CD34 antibody or binding fragment thereof, respectively; orwherein the first portion of the anti-G6B antibody or binding fragment thereof and the first portion of the anti-CD34 antibody or binding fragment thereof are independently the VL of the anti-G6B antibody or binding fragment thereof and the VL of the anti-CD34 antibody or binding fragment thereof, respectively, and the second portion of the anti-G6B antibody or binding fragment thereof and the second portion of the anti-CD34 antibody or binding fragment thereof are independently the VH of the anti-G6B antibody or binding fragment thereof and the VH of the anti-CD34 antibody or binding fragment thereof, respectively.

94. The composition of any one of claims 44-93, wherein the anti-G6B antibody or binding fragment thereof, the anti-CD34 antibody or binding fragment thereof, or any combination thereof is independently a murine, human, or humanized antibody or binding fragment thereof.

95. The composition of any one of claims 44-94, wherein the multifunctional molecule further comprises any one selected from the group consisting of an immune cell engager, a cytokine molecule, a modulator of a cytokine molecule, a stromal modifying moiety, a tumor targeting moiety, and any combination thereof, wherein the immune cell engager is selected from the group consisting of a T cell engager, an NK cell engager, a B cell engager, a macrophage cell engager, and a dendritic cell engager.

96. The composition of claim 95, wherein the immune cell engager, the cytokine molecule, the modulator of a cytokine molecule, the stromal modifying moiety, the tumor targeting moiety, or any combination thereof is linked to the first polypeptide, the second polypeptide, the third polypeptide, the fourth polypeptide, or any combination thereof.

97. The composition of claim 96, wherein the immune cell engager, the cytokine molecule, the modulator of a cytokine molecule, the stromal modifying moiety, the tumor targeting moiety, or any combination thereof is within a single contiguous polypeptide chain of the first polypeptide, the second polypeptide, the third cytokine polypeptide, or the fourth cytokine polypeptide to which the immune cell engager, the cytokine molecule, the modulator of a cytokine molecule, the stromal modifying moiety, the tumor targeting moiety, or any combination thereof is linked.

98. The composition of any one of claims 96-97, wherein the immune cell engager, the cytokine molecule, the modulator of the cytokine molecule, the stromal modifying moiety, the tumor targeting moiety, or any combination thereof is linked to the first polypeptide, the second polypeptide, the third cytokine polypeptide, or the fourth cytokine polypeptide by a linker.

99. The composition of any one of claims 18-22, 39-43, and 95-98, wherein the immune cell engager is: the T cell engager, wherein the T cell engager binds to any one selected from the group consisting ofCD3, TCRa, TCR(3, TCRy, TCR^, ICOS, CD28, CD27, HVEM, LIGHT, CD40, 4-1BB, 0X40, DR3, GITR, CD30, TIM1, SLAM, CD2, CD226, and any combination thereof; the NK cell engager, wherein the NK cell engager is an antigen binding domain or a ligand that binds to any one selected from the group consisting of NKp30, NKp40, NKp44, NKp46, NKG2D, DNAM1,DAP 10, CD 16, CRTAM, CD27, PSGL1, CD96, CD 100, NKp80, CD244, SLAMF6, SLAMF7, KIR2DS2, KIR2DS4, KIR3DS1, KIR2DS3, KIR2DS5, KIR2DS1, CD94, NKG2C, NKG2E, CD160, and any combination thereof; the B cell engager, wherein the B cell engage is selected from the group consisting of CD40L, OX40L, a CD70 ligand, an 0X40 antibody molecule, a CD40 antibody molecule, a CD70 antibody molecule, and any combination thereof; the macrophage cell engager, wherein the macrophage cell engager is selected from the group consisting of a CD2 agonist, CD40L, OX40L, the 0X40 antibody molecule, the CD40 antibody molecule, the CD70 antibody molecule, a Toll-like receptor agonist or fragment thereof, CD47, a STING agonist, and any combination thereof; or the dendritic cell engager, wherein the dendritic cell engager is selected from the group consisting of the CD2 agonist, the 0X40 antibody, the OX40L, a 4 IBB agonist, the Toll-like receptor agonist or the fragment thereof, a CD47 agonist, the STING agonist, and any combination thereof.

100. The composition of any one of claims 18-22, 39-43, and 95-98, wherein the cytokine molecule is selected from the group consisting of interleukin-2 (IL-2) or functional fragment or functional variant thereof, interleukin-7 (IL- 7) or functional fragment or functional variant thereof, interleukin- 12 (IL- 12) or functional fragment or functional variant thereof, interleukin- 15 (IL- 15) or functional fragment or functional variant thereof, interleukin- 18 (IL- 18) or functional fragment or functional variant thereof, interleukin -21 (IL-21) or functional fragment or functional variant thereof, interferon gamma or functional fragment or functional variant thereof, and any combination thereof.

101. The composition of any one of claims 18-22, 39-43, and 95-98, wherein the modulator of a cytokine molecule is a TGF-beta inhibitor.

102. The composition of claim 101, wherein the TGF-beta inhibitor comprises an amino acid sequence with at least 70% sequence identity to any one sequence selected from the group consisting of the extracellular domain sequences of SEQ ID NOs: 93-99, 106, 107, 117-119, 120-126, and 200.

103. The composition of claim 101, wherein the TGF-beta inhibitor comprises an amino acid sequence of any one of the extracellular domain sequences of SEQ ID NOs: 93-99, 106, 107, 117-119, 120-126, and 200.

104. The composition of claim 101, wherein the TGF-beta inhibitor comprises an amino acid sequence with at least 70% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 100- 105 and 108.

105. The composition of claim 101, wherein the TGF-beta inhibitor comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 100-105 and 108.

106. The composition of claim 101, wherein the multifunctional molecule comprises an amino acid sequence with at least 70% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 192-199.

107. The composition of claim 101, wherein the multifunctional molecule comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 192-199.

108. The composition of any one of claims 101-107, wherein the TGF-beta inhibitor targets the bone marrow stromal niche when administered to a subject.

109. The composition of any one of claims 101-108, wherein the TGF-beta inhibitor targets a malignant haematopoietic stem cell or a progenitor cell in the bone marrow stromal niche when administered to a subject.

110. The composition of any one of claims 18-22, 39-43, and 95-98, wherein the tumor targeting moiety binds to any one selected from the group consisting of CD41, P-selectin, Clec2, cKIT, FLT3, MPL, ITGB3, ITGB2, GP5, GP6, GP9, GP1BA, DSC2, FCGR2A, TNFRSF10A, TNFRSF10B, or TM4SF1, alphafetoprotein (AFP), carcinoembryonic antigen (CEA), CA-125, MUC-1, epithelial tumor antigen (ETA), tyrosinase, melanoma-associated antigen (MAGE), HER2, B-cell maturation antigen (BCMA), mesothelin, CD 19, and any combination thereof.

111. The composition of any one of claims 18-22, 39-43, and 95-98, wherein the stromal modifying moiety comprises an enzyme molecule that degrades a tumor stroma or extracellular matrix (ECM).

112. The composition of claim 111, wherein the enzyme molecule is selected from the group consisting of a hyaluronidase molecule or variant thereof, a collagenase molecule or variant thereof, a chondroitinase molecule or variant thereof, a matrix metalloproteinase molecule or variant thereof, and any combination thereof.

113. The composition of claim 112, wherein the stromal modifying moiety comprises the hyaluronidase molecule or variant thereof, and wherein the hyaluronidase molecule is selected from the group consisting of hyaluronidase- 1 (HYAL1) or variant thereof, hyaluronidase -2 (HYAL2) or variant thereof, and hyaluronidase PH-20 (PH-20 / SPAM1) or variant thereof.

114. The composition of claim 113, wherein the HYAL1 or variant thereof comprises a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 67.

115. The composition of claim 113, wherein the PH-20 / SPAM1 or variant thereof comprises a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 66.

116. The composition of claim 111, wherein the stromal modifying moiety comprises a hyaluronan degrading enzyme, an agent that inhibits hyaluronan synthesis, an antibody molecule against hyaluronic acid, or any combination thereof.

117. The composition of claim 116, wherein the agent that inhibits hyaluronan synthesis comprises a sense or an antisense nucleic acid molecule against a HA synthase, a small molecule drug, or any combination thereof.

118. The composition of claim 112, wherein the collagenase molecule or variant thereof is collagenase molecule IV or variant thereof.

119. The composition of claim 118, wherein the collagenase molecule IV comprises a sequence having at least 70% sequence identity to the sequence of SEQ ID NO: 68.

120. The composition of any one of claims 44-119, wherein the linker is selected from the group consisting of a cleavable linker, a non-cleavable linker, a peptide linker, a flexible linker, a rigid linker, a helical linker, and a non-helical linker.

121. The composition of claim 120, wherein the linker is the peptide linker comprising any one of the sequences selected from the group consisting of SEQ ID NOs: 69-72, 295, and 296.

122. A pharmaceutical composition comprising the composition of any one of claims 1-121, and a pharmaceutically acceptable carrier, excipient, or stabilizer.

123. A method of treating a condition or disease in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the composition of any one of claims 1-121 or the pharmaceutical composition of claim 122, wherein the administering is effective to treat the condition or disease in the subject.

124. The method of claim 123, wherein the condition or disease is cancer.

125. The method of claim 124, wherein the cancer is a solid cancer.

126. The method of claim 125, wherein the solid cancer is ovarian cancer, rectal cancer, stomach cancer, testicular cancer, cancer of the anal region, uterine cancer, colon cancer, renal-cell carcinoma, liver cancer, lung cancer, small intestine cancer, esophagus cancer, melanoma, Kaposi's sarcoma, cancer of the endocrine system, thyroid gland cancer, parathyroid gland cancer, adrenal gland cancer, bone cancer, pancreatic cancer, skin cancer, head cancer, neck cancer, brain stem glioma, pituitary adenoma, epidermoid cancer, cervix squamous cell cancer, fallopian tube carcinoma, endometrium carcinoma, vagina cancer, soft tissue sarcoma, urethra cancer, ureter cancer, vulva carcinoma, penis cancer, breast cancer, bladder cancer, kidney cancer, renal pelvis cancer, spinal axis tumor, central nervous system (CNS) neoplasm, primary CNS lymphoma, tumor angiogenesis, cancer of metastatic lesions, or any combination thereof.

127. The method of claim 126, wherein the lung cancer is small cell lung cancer, or non-small cell lung cancer.

128. The method of claim 126, wherein the melanoma is cutaneous malignant melanoma, or intraocular malignant melanoma129. The method of claim 126, wherein the pancreatic cancer is pancreatic adenocarcinoma.

130. The method of claim 124, wherein the cancer is a myeloproliferative neoplasm.

131. The method of claim 130, wherein the myeloproliferative neoplasm is primary or idiopathic myelofibrosis (MF), essential thrombocythemia or thrombocytosis (ET), polycythemia vera (PV), chronic myelogenous leukemia (CML), or myelofibrosis.

132. The method of claim 131, wherein the cancer is essential thrombocythemia or thrombocytosis (ET), and the subject also has secondary myelofibrosis.

133. The method of claim 131, wherein the cancer is polycythemia vera (PV), and the subject also has secondary myelofibrosis.

134. The method of claim 124, wherein the cancer is a hematological cancer.

135. The method of claim 134, wherein the hematological cancer is a leukemia or a lymphoma.

136. The method of claim 135, wherein the leukemia is acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), hairy cell leukemia, acute monocytic leukemia (AMoL), chronic myelomonocytic leukemia (CMML), juvenile myelomonocytic leukemia (JMML), or large granular lymphocytic leukemia.

137. The method of claim 135, wherein the lymphoma is AIDS-related lymphoma, cutaneous T-cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, chronic myeloproliferative neoplasm, Langerhans cell histiocytosis, multiple myeloma / plasma cell neoplasm, myelodysplastic syndrome, myelodysplastic neoplasm, primary central nervous system lymphoma, or myeloproliferative neoplasm.

138. The method of claim 137, wherein the Hodgkin lymphoma is classical Hodgkin lymphoma, or nodular lymphocyte-predominant Hodgkin lymphoma.

139. The method of claim 137, wherein the non-Hodgkin lymphoma is B-celi non-Hodgkin lymphoma, or T-cell non-Hodgkin lymphoma.

140. The method of claim 139, wherein B-cell non-Hodgkin lymphoma is Burkitt lymphoma, small lymphocytic lymphoma (CLL / SLL), diffuse large B-cell lymphoma, follicular lymphoma, immunoblastic large cell lymphoma, precursor B -lymphoblastic lymphoma, mantle cell lymphoma, or Waldenstrom macroglobulinemia.

141. The method of claim 139, wherein T-cell non-Hodgkin lymphoma is mycosis fungoides, anaplastic large cell lymphoma, Sezary' syndrome, or precursor T-lymphoblastic lymphoma.

142. The method of any one of claims 123-141, wherein the subject is human.

143. The method of any one of claims 123-142, further comprising administering a second therapeutic agent or therapy to the subject.

144. The method of claim 143, wherein the second therapeutic agent or therapy comprises a chemotherapeutic agent, a biologic agent, a viral cancer therapeutic agent, an RNAi agent, an antisense RNA agent, a hormonal therapy, radiation, surgery, or any combination thereof.

145. The method of any one of claims 143-144, wherein the second therapeutic agent or therapy is administered in combination with the composition of any one of claims 1-121 or the pharmaceutical composition of claim 122 previously, concurrently, or sequentially.

146. A method of targeting a TGF-beta inhibitor to a bone marrow stromal niche in a subject, the method comprises administering the composition of any one of claims 101-105 to a subject in need thereof, wherein the TCF-beta inhibitor is targeted to the bone marrow stromal niche in the subject.

147. The method of claim 146, wherein the TGF-beta inhibitor is targeted to a malignant haematopoietic stem cell or a progenitor cell in the bone marrow stromal niche in the subject.

Images